CN101370806A - Substituted 4-phenylpiperidines - Google Patents

Abstract

The application relates to substituted 4-phenylpiperidines of the general formula and their salts, preferably their pharmaceutically acceptable salts, in which R<2>, R<3>, W and X have the meanings explained in the description, a process for their preparation and the use of these compounds as medicines, especially as renin inhibitors.

Description

Substituted 4-phenylpiperidines

technical field

The present invention relates to novel substituted 4-phenylpiperidines, a process for their preparation and the use of the compounds as medicaments, especially as renin inhibitors.

Background of the invention

Piperidine derivatives useful as medicines are disclosed, for example, in WO97/09311. However, particularly with regard to renin inhibitors, there is still a need for highly potent active ingredients. In this context the focus is on improving pharmacokinetic properties. Such properties which are associated with better bioavailability are for example absorption, metabolic stability, solubility or lipophilicity.

Detailed description of the invention

The present invention therefore relates primarily to substituted 4-phenylpiperidines of the general formula:

in

(A) R ¹ is a heterocyclic group substituted by oxo or oxide, or a heterocyclic group represented by the following (B) or (C), especially azepanyl (azepanyl), benzo[1 , 3] Dioxolyl (dioxolyl), benzofuryl, benzimidazolyl, 4H-benzo[1,4]oxazinyl, benzoxazolyl, 4H-benzo[1 , 4] Thiazinyl, quinolinyl, benzopyranyl, dihydro-benzo[e][1,4]diazepinyl (diazepinyl), dihydrobenzofuranyl, 3, 4-dihydro-2H-benzo[1,4]oxazinyl, dihydro-3H-benzo[1,4]oxazinyl, dihydrobenzo[d][1,3]oxazinyl, 3,4-Dihydro-2H-benzo[1,4]thiazinyl, dihydro-2H-1λ6-benzo[1,4]thiazinyl, dihydro-1H-quinazolinyl, 1a, 7b-Dihydro-1H-cyclopropane[c]benzopyranyl, dihydroimidazolyl, 1,3-dihydroindolyl, 2,3-dihydroindolyl, dihydro-1H-pyrido [2,3-b][1,4]oxazinyl, indazolyl, indolyl, 3H-isobenzofuryl, [1,5]naphthyridine, oxazolyl, 2,3 -diazanaphthyl, piperidinyl, pyrazolyl, 1H-pyrido[2,3-b][1,4]oxazinyl, pyridinyl, 1H-pyrrolidinyl, 1H-pyrrolo[2 , 3-b]pyridyl, pyrrolyl, tetrahydrobenzo[e][1,4]diazepanyl, 3H-thieno[2,3-d]pyrimidinyl, tetrahydro-quinoxa Linyl, 1,1a,2,7b-tetrahydrocyclopropane[c]benzopyranyl, tetrahydropyranyl or triazinyl; or

(B) R ¹ is an aryl group substituted by the following groups: 1-4-acetamidinyl (acetamidinyl)-C _1-8 alkyl, acyl-C _1-8 alkoxy-C _1-8 alkyl, (N-acyl)-C _1-8 alkoxy- _C 1-8 alkylamino, C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkoxy, C _1-8 Alkoxy-C _1-8 alkoxy-C 1-8 alkyl, C _1-8 alkoxy _- C _1-8 alkyl, (NC _1-8 alkoxy)-C _1-8 alkyl Aminocarbonyl-C _1-8 alkoxy, (NC _1-8 alkoxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkane Base-carbamoyl, C _1-8 alkoxy-C 1-8 alkylcarbonyl, C _1-8 alkoxy-C _1-8 alkylcarbonylamino, 1-C _{1-8 alkoxy} -C _1-8 alkylimidazol-2-yl, 2-C _1-8 alkoxy-C _1-8 alkyl-4-oxoimidazol-1-yl, 1-C _1-8 alkoxy-C _{1 -8} -Alkyl tetrazol-5-yl, 5-C _1-8 alkoxy-C _1-8 -alkyl tetrazol-1-yl, 6-alkoxy-aminocarbonyl-C _1-8 alkane Oxygen, C _1-8 alkoxyaminocarbonyl-C _1-8 alkyl, C _1-8 alkoxycarbonyl, C _1-8 alkoxycarbonyl-C _1-8 alkoxy, C _1-8 Alkoxycarbonyl-C _1-8 alkyl, C _1-8 alkoxycarbonylamino-C _1-8 alkoxy, C _1-8 alkoxycarbonylamino-C _1-8 alkyl, C _{1- 8} alkyl, (NC _1-8 alkyl)-C _1-8 alkoxy-C _1-8 alkylcarbamoyl, (NC _1-8 alkyl)-C _1-8 alkoxy-C _{1 -8} alkylcarbonylamino, (NC _1-8 alkyl)-C _1-8 alkoxycarbonylamino, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkoxy Base, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkyl, (NC _1-8 alkyl)-C _1-8 alkylsulfonylamino-C _1-8 Alkoxy, (NC _1-8 alkyl)-C _1-8 alkylsulfonylamino-C _1-8 alkyl, C _1-8 alkyl amidinyl (amidinyl), C _1-8 alkylaminocarbonyl -C _1-8 alkoxy, di-C _1-8 alkylaminocarbonyl-C _1-8 alkoxy, C _1-8 alkylaminocarbonyl-C _1-8 alkoxy-C _1-8 alkane Base, C _1-8 alkylaminocarbonyl-C _1-8 alkyl, C _1-8 alkylaminocarbonylamino-C _{1-8 alkoxy, C 1-8 alkylaminocarbonylamino} -C _1-8 Alkyl, two-C _1-8 alkylaminocarbonyl- _C 1-8 alkyl, C _1-8 alkylamino-C _2-8 alkoxy, two-C _1-8 alkylamino-C _{2- 8} alkoxy, C _1-8 alkylamino-C _1-8 alkyl, two- C _1-8 alkylamino-C _1-8 alkyl, C _1-8 alkylcarbamoyl, di-C _1-8 alkylcarbamoyl, C _0-8 alkylcarbonylamino-C _1-8 Alkoxy, C _0-8 alkylcarbonylamino, C _0-8 alkylcarbonylamino-C _1-8 alkyl, C _1-8 alkylcarbonyloxy-C _1-8 alkoxy, C _{1- 8} Alkylcarbonyloxy-C _1-8 Alkyl, C _1-8 Alkylsulfonyl, C _1-8 Alkylsulfonyl-C _1-8 Alkoxy, C _1-8 Alkylsulfonyl-C _1-8 alkyl, C _1-8 alkylsulfonylamino-C _1-8 alkoxy, C _1-8 alkylsulfonylamino-C _1-8 alkyl, carbamoyl, carbamoyl-C _1-8 alkoxy, carbamoyl-C _1-8 alkyl, carboxy-C _1-8 alkoxy, carboxy-C _1-8 alkoxy-C _1-8 alkyl, carboxy-C _{1- 8} alkyl, cyano, cyano-C _1-8 alkoxy, cyano-C _1-8 alkyl, C _3-8 cycloalkyl-C _1-8 alkoxy, C _3-8 cycloalkane Base- _{C 1-8} alkyl, C _3-8 cycloalkylcarbonylamino-C 1-8 alkoxy, C _3-8 cycloalkylcarbonylamino-C _1-8 alkyl, O, N-dimethyl Base hydroxyamino-C _1-8 alkyl, halogen _, hydroxy-C _1-8 alkoxy-C 1-8 alkoxy, hydroxy-C _1-8 alkoxy-C _1-8 alkyl, hydroxy- C _1-8 alkyl, (N-hydroxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkoxy, (N-hydroxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkane Base, (N-hydroxy) aminocarbonyl-C _1-8 alkoxy, (N-hydroxy) aminocarbonyl-C _1-8 alkyl, 2-oxooxazolidinyl-C _1-8 alkoxy, 2-Oxooxazolidinyl-C _1-8 alkyl, O-methyloximyl (methyloximyl)-C _1-8 alkyl, polyhalogenated-C _1-8 alkoxy or polyhalogenated-C _1-8 alkyl; or

(C) R ¹ is aryl substituted by the following groups: 3-acetamidomethylpyrrolidinyl, 3-C _1-8 alkoxy-C _1-8 alkyl-pyrrolidinyl, 3,4 -Dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4,4-dioxo Thiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4-hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolyl-alkoxy, imidazolidinyl Base, 2-methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3-methyl-[1,2,4]-oxadiazol-5-ylalkoxy, 5-methyl- [1,2,4]-oxadiazol-3-ylalkoxy, 3-methyl-[1,2,4]-oxadiazol-5-ylalkyl, 5-methyl-[1, 2,4]-Oxadiazol-3-ylalkyl, 4-methylpiperazinyl, 5-methyltetrazol-1-ylalkoxy, 5-methyltetrazol-1-ylalkyl, Morpholinyl, [1,2,4]-oxadiazol-5-ylalkoxy, [1,2,4]-oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy , oxazol-4-ylalkyl, 2-oxo-[1,3]-oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxo-piperidinyl, 2-oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxotetrahydropyrimidinyl, 4-oxothiomorpholinyl, piperrolidinyl Azinyl, piperidinyl, pyrrolidinyl, pyrrolyl, [1,2,4]-triazol-1-yl-alkoxy, [1,2,4]-triazol-4-ylalkoxy , [1,2,4]-triazol-1-ylalkyl, [1,2,4]-triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazole-2- ylalkoxy, tetrazol-5-ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy , thiazol-4-ylalkyl or thiomorpholinyl; or

(D) When X is -O-CHR ⁶ -CO-NR ⁴ -R ¹ or -O-CHR ⁶ -CO-NR ⁴ -Z, wherein Z is Alk-R ¹ , wherein Alk is C _1-8 alkylene When radical, R ¹ is aryl; or

(E) When X is -OZ, wherein Z is Alk-NR ⁴ -R ¹ , or X is -Z, wherein Z is -Alk-NR ⁴ -R ¹ , wherein Alk is a C _1-8 alkylene group, R ¹ is aryl;

R ² a) when W is cyano, R ² is absent; or

b) When W is -O- or -S-, R ² is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy-C _1-8 Alkyl, C _1-8 alkoxy-C _3-8 cycloalkyl-C _1-8 -alkyl, C _1-8 alkylthio-C _1-8 alkyl, C _1-8 alkylsulfonyl -C _1-8 alkyl;

R ³ a) is halogen- and/or hydroxy-substituted C _1-8 alkoxy, halogen- and/or hydroxy-substituted C _1-8 alkoxy-C _1-8 alkoxy, branched C _1-8 alkoxy-C _1-8 alkoxy, optional N-mono or N, N-di-C _1-8 -alkylated amino-C _1-8 alkoxy, optional NC _{1- 8} Alkylated C _1-8 alkoxy-C _1-8 alkylamino-C _1-8 alkoxy, optional N-mono or N, N-di-C _1-8 alkylated amino-C _0-8 -Alkylcarbonyl-C _1-8 Alkoxy, Hydroxy-C _0-8 -Alkylcarbonyl-C _0-8 Alkoxy, C _1-8 Alkoxy-C _0-8 Alkylcarbonyl -C _0-8 alkoxy, C _1-8 -alkylcarbonylamino-C _1-8 alkoxy, cyano-C _1-8 alkoxy, substituted C _3-8 cycloalkyl-C _{0 -8} alkoxy, heterocyclyl-C _0-8 alkoxy, optional NC _1-8 alkylated heterocyclyl-C _0-8 alkylamino-C _0-8 alkylcarbonyl-C _{0- 8} alkoxyl, C _1-8 alkyl-sulfonyl-C _1-8 alkoxyl, C _2-8 alkynyloxy, heterocyclyl-C _2-8 alkynyloxy, optional N-single or N , N-di-C _1-8 alkylated amino-C _2-8 alkynyloxy, N-single or N, N-di-C _1-8 alkylated aminocarbonyl-C _2-8 alkynyloxy, Heterocyclylcarbonyl-C _0-8 alkoxy, optional N-mono or N, N-di-C _1-8 alkylated amino-C _1-8 alkyl, optional NC _1-8 alkylated C _1-8 alkoxy-C _1-8 alkylamino-C _1-8 alkyl, optionally N-mono or N, N-di-C _1-8 alkylated and optionally hydroxy substituted amino- C _0-8 alkyl-carbonyl-C _0-8 alkyl, optional NC _1-8 alkylated heterocyclyl-C _0-8 alkylamino-C _0-8 alkylcarbonyl-C _0-8 alkane C _1-8 alkoxy-C _1-8 alkyl optionally substituted with halogen or hydroxy, optionally substituted hydroxy-C _1-8 alkyl with halogen or hydroxy, optionally NC _1-8 alkylated hydroxy -C _1-8 alkylamino-C _1-8 alkyl, heterocyclylcarbonyl-C _0-8 alkyl, heterocyclylcarbonyl-C _0-8 alkylamino-C _1-8 alkyl, heterocyclic Base-C _1-8 alkyl, C _1-8 alkoxycarbonylamino-C _1-8 alkyl, optionally halogen substituted heterocyclyl-C _0-8 alkylcarbonylamino-C _1-8 alkyl , optionally halogen substituted C _3-8 cycloalkyl-C _0-8 alkylcarbonylamino-C _1-8 alkyl or optionally halogen substituted C _1-8 alkylcarbonylamino-C _1-8 alkyl ; or otherwise

b) If -WR ² is not C _1-8 alkoxy, then R ³ is hydroxyl, unsubstituted C _1-8 alkoxy, unsubstituted unbranched C _1-8 alkoxy-C _{1- 8} -alkoxy or unsubstituted C _3-8 cycloalkyl-C _0-8 alkoxy;

R ⁴ is acyl, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkyl, aryl-C _1-8 alkyl, C _3-8 cycloalkyl-C _0-8 alkane base or hydrogen;

R ⁵ is C _1-8 alkoxycarbonyl-C _1-8 alkyl, C _1-8 alkyl, carboxy-C _1-8 alkyl or hydrogen;

R ⁶ is acyl, C _2-8 alkenyl, C _1-8 alkyl, aryl-C _1-8 alkyl or hydrogen;

X is Z, -OZ or -SZ, where a bond derived from an oxygen or sulfur atom yields a saturated C atom of the group Z, or is a group -CHR ⁶ -Z, -CHOR ⁴ -Z, -O-CO-Z , -O-CO-R ¹ , -CO-Z, -C=NOR ⁵ -Z, -O-CHR ⁶ -Z, -O-CHR ⁶ -CO-NR ⁴ -Z, -O-CHR ⁶ -CO -NR ⁴ -R ¹ , or -O-CHR ⁶ -R ¹ ;

W is -O-, -S- or cyano;

Z is C _1-8 -Alk-R ¹ , C _2-8 alkenylene-R ¹ , hydroxyl-substituted -Alk-R ¹ , -OR ¹ , -SR ¹ , -O-Alk-R ¹ , - S-Alk-R ¹ , -Alk-OR ¹ , -Alk-SR ¹ or -Alk-NR ⁴ -R ¹ , wherein Alk is C _1-8 alkylene; and wherein

(a) If Z is -OR ¹ or -SR ¹ , then X is -CH-R ⁶ -Z

(b) if Z is -O-Alk-R ¹ or -S-Alk-R ¹ , then X is -CH-R ⁶ -Z; and

(c) if X is Z, then Z is C _2-8 alkenylene -R ¹ , -Alk-OR ¹ , -Alk-SR ¹ or -Alk-NR ⁴ -R ¹ ;

and their salts, preferably their pharmaceutically acceptable salts.

C _1-8 Alkyl and alkoxy groups can be linear or branched. Examples of _C1-8 alkyl and alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. The C _1-8 alkylenedioxy groups are preferably methylenedioxy, ethylenedioxy and propylenedioxy. Examples of C _1-8 alkanoyl groups are acetyl, propionyl and butyryl. Cycloalkyl is a saturated cyclic hydrocarbon radical having 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, Bicyclo[2.2.2]octyl and adamantyl. Cycloalkyl can be unsubstituted or monosubstituted or polysubstituted, for example by C _1-8 alkanoyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _{1-8 8} alkoxy-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxycarbonylamino, C _1-8 alkyl, C _0-8 alkane C _1-8 alkylcarbonylamino, C 1-8 alkylcarbonyloxy, C _1-8 alkylenedioxy, optional N-mono or N, N-di-C _1-8 alkylated amino, aryl, any Select N-mono or N, N-di-C _1-8 alkylated carbamoyl, optionally esterified carboxy, cyano, C _3-8 cycloalkoxy, halogen, heteroaryl, heterocyclyl , hydroxyl, oxo, polyhalo-C _1-8 alkoxy or polyhalo-C _1-8 alkyl monosubstituted or disubstituted. The C _1-8 alkylene group may be linear or branched and is, for example, methylene, ethylene, propylene, 2-methylpropylene, 2-methylbutylene, 2-methyl groups - 2-propylene, 2-butylene, 3-butylene, 2-propylene, tetra-, penta- and hexa-methylene; C _2-8 alkenylene groups are e.g. vinylene and propenylene; a C _2-8 alkynylene group is, for example, ethynylene; an acyl group is an alkanoyl group, preferably a C _1-8 alkanoyl group, or an aroyl group, such as benzoyl. Aryl denotes a mono- or polynuclear aryl group which may be mono- or polysubstituted, for example phenyl, substituted phenyl, naphthyl, substituted naphthyl, tetrahydronaphthyl or substituted tetrahydronaphthyl. Examples of substituents on such aryl groups are C _1-8 alkyl, polyhalo-C _1-8 alkoxy, polyhalo-C _1-8 alkyl, nitroamino, C _1-8 alkenes C _1-8 alkoxy, C _1-8 alkylcarbonyloxy, hydroxyl, halogen, cyano, carbamoyl, carboxyl and C _1-8 alkylenedioxy, and optionally halogen-, C _1-8 alkyl-, C _1-8 alkoxy- or dihydroxy-C _1-8 alkylaminocarbonyl-substituted phenyl, phenoxy, phenylthio, phenyl-C _1-8 alkane Base or phenyl-C _1-8 alkoxy. Further examples of substituents on aryl or heterocyclyl groups are C _1-8 alkoxycarbonylphenyl, hydroxy-C _1-8 alkylphenyl, benzyloxy, pyridylcarbonylamino-C _{1 -8} alkyl, C _2-8 alkenyloxy, C 1-8 alkoxy-C _1-8 alkoxy, C _1-8 alkoxy _- C _1-8 alkoxy-C _1-8 Alkyl, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-C _1-8 alkoxy, cyclopropyl -C _1-8 alkyl, cyclopropyl-C _1-8 alkoxy, hydroxyl-C _1-8 alkoxy, carbamoyloxy-C _1-8 alkoxy, pyridylcarbamoyloxy Base-C _1-8 alkoxy, benzoyloxy-C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _0-8 alkylcarbonylamino, C _0-8 alkylcarbonylamino -C _1-8 alkyl, C _0-8 alkylcarbonylamino-C _1-8 alkoxy, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkyl, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkoxy, C _3-8 -cycloalkylcarbonylamino-C _1-8 alkyl, C _3-8 cycloalkane Carbonylamino-C _1-8 alkoxy, C 1-8 alkoxy- _{C 1-8} alkyl, hydroxy-C _1-8 alkyl, hydroxy-C _1-8 alkoxy-C _1-8 Alkyl, hydroxy-C _1-8 alkoxy-C _1-8 alkoxy, C _1-8 alkoxycarbonylamino-C _1-8 alkyl, C _1-8 alkoxycarbonylamino-C _{1 -8} alkoxy, C _1-8 alkylaminocarbonylamino-C _1-8 alkyl, C _1-8 alkylaminocarbonylamino-C _1-8 alkoxy, C _1-8 alkylaminocarbonyl- C _1-8 alkyl, C _1-8 alkylaminocarbonyl-C _1-8 alkoxy, C _1-8 alkylaminocarbonyl-C _1-8 alkoxy-C _1-8 alkyl, di- C _1-8 alkylaminocarbonyl-C _1-8 alkyl, di-C _1-8 alkylaminocarbonyl-C _{1-8 alkoxy, C 1-8 alkylcarbonyloxy} -C _1-8 alkane Base, C _1-8 alkylcarbonyloxy-C _1-8 alkoxy, cyano-C _1-8 alkyl, cyano-C _1-8 alkoxy, 2-oxooxazolidinyl- C _1-8 alkyl, 2-oxooxazolidinyl-C _1-8 alkoxy, C _1-8 alkoxycarbonyl-C _1-8 alkyl, C _1-8 alkoxycarbonyl-C _1-8 alkoxy, C _1-8 alkylsulfonylamino-C _1-8 alkyl, C _1-8 alkylsulfonylamino-C _1-8 alkoxy, (NC _1-8 alkyl) -C _1-8 alkylsulfonylamino-C _1-8 alkyl, (NC _1-8 alkyl)-C _1-8 alkylsulfonylamino-C _1-8 alkoxy, C _1-8 alkane Amino-C _1-8 alkyl, C _1-8 alkylamino-C _2-8 alkoxy, di- _{C 1-8} alkylamino-C _1-8 alkyl, di -C _1-8 alkylamino-C _2-8 alkoxy, _{C 1-8} alkylsulfonyl-C 1-8 alkyl, C _1-8 alkylsulfonyl-C _1-8 alkoxy, Carboxy-C _1-8 alkyl, carboxy- _C 1-8 alkoxy, carboxy-C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl Carbonyl, acyl-C _1-8 alkoxy-C _1-8 alkyl, (NC _1-8 alkyl)-C _1-8 alkoxycarbonylamino, (N-hydroxyl)-C _1-8 alkyl Aminocarbonyl-C _1-8 alkyl, (N-hydroxyl)-C _1-8 alkylaminocarbonyl-C _1-8 alkoxyl, (N-hydroxyl) aminocarbonyl-C _1-8 alkyl, (N -Hydroxy)aminocarbonyl-C _1-8 alkoxy, C _1-8 alkoxyaminocarbonyl-C _1-8 alkyl, 6-alkoxyaminocarbonyl-C _1-8 alkoxy, (NC _{1 -8} alkoxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkyl, (NC _1-8 alkoxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkoxy, (N-acyl)-C _1-8 alkoxy-C _1-8 alkylamino, C _1-8 alkoxy-C _1-8 alkylcarbamoyl, (NC _1-8 alkyl)-C _1-8 alkoxy-C _1-8 alkylcarbamoyl, C _1-8 alkoxy-C _1-8 alkylcarbonyl, C _1-8 alkoxy-C _1-8 alkylcarbonylamino, (NC _1-8 alkyl)-C _{1-8 alkoxy-C 1-8 alkylcarbonylamino, 1-C 1-8 alkoxy} -C _1-8 alkylimidazol-2-yl, 1- C _1-8 alkoxy-C _1-8 alkyl tetrazol-5-yl, 5-C _1-8 alkoxy-C _1-8 alkyl tetrazol-1-yl, 2-C _1-8 Alkoxy-C _1-8 alkyl-4-oxoimidazol-1-yl, carbamoyl-C _1-8 alkyl, carbamoyl-C _1-8 alkoxy, C _1-8 alkyl Carbamoyl, Di-C _1-8 Alkylcarbamoyl, C _1-8 Alkylsulfonyl, C _1-8 Alkylamidino, Acetamido-C _1-8 Alkyl, O-methyloxime Base-C _1-8 alkyl, O, N-dimethylhydroxylamino-C _1-8 alkyl, C _3-8 cycloalkyl-C _1-8 alkanoyl, aryl-C _1-8 chain Alkanoyl, heterocyclyl-C _1-8 alkanoyl; and optionally halogen-, C _1-8 alkyl-, C _1-8 alkoxy- or dihydroxy-C _1-8 alkylaminocarbonyl- Substituted pyridyl, pyridyloxy, pyridylthio, pyridylamino, pyridyl-C _1-8 alkyl, pyridyl-C _1-8 alkoxy, pyrimidyl, pyrimidyloxy, pyrimidyl Thio, pyrimidinylamino, pyrimidinyl-C _1-8 alkyl, pyrimidinyl-C _1-8 alkoxy, thienyl, thienyl-C _1-8 alkyl, thienyl-C _1-8 alkoxy Base, furyl, furyl-C _1-8 alkyl, furyl-C _1-8 alkoxy.

The term heterocyclyl denotes mono-, bi- or polycyclic saturated and unsaturated heterocyclic radicals having 1 to 4 nitrogen and/or 1 or 2 sulfur or oxygen atoms, which may be monosubstituted or polysubstituted, in particular monosubstituted, Disubstituted or trisubstituted. The term heterocyclyl further includes the aforementioned oxo-substituted groups. A heterocyclyl group comprising a nitrogen atom may be bonded to the remainder of the molecule via the N atom or via the C atom.

Examples of unsaturated heterocyclyl groups are benzo[1,3]dioxy, benzofuryl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzothienyl, quinazoline Base, quinolinyl, quinoxalinyl, benzopyranyl, dihydrobenzofuranyl, 1,3-dihydrobenzimidazolyl, 3,4-dihydro-2H-benzo[1,4 ]oxazinyl, dihydro-3H-benzo[1,4]oxazinyl, 1,4-dihydrobenzo[d][1,3]oxazinyl, dihydro-2H-benzo[1 ,4] Thiazinyl, 3,4-dihydro-1H-quinazolinyl, 3,4-dihydro-1H-quinolinyl, 2,3-dihydroindolyl, dihydro-1H-pyridine And[2,3-b][1,4]oxazinyl, 1,1-dioxodihydro-2H-benzo[1,4]thiazinyl, furyl, imidazolyl, imidazo[1 , 5-a]pyridyl, imidazo[1,2-a]pyrimidinyl, indazolyl, indolyl, isobenzofuryl, isoquinolyl, [1,5]diazinyl, Oxazolyl, 1-oxopyridyl, 2-oxobenzoimidazolyl, 3-oxo-4H-benzo[1,4]oxazinyl, 2-oxobenzoxazolyl, 3-oxo Substitute-4H-benzo[1,4]thiazinyl, 2-oxo-1H-quinolyl, 2-oxo-benzopyranyl, 2-oxodihydrobenzo[e][1 ,4] Diazepanyl, 2-oxo-1,3-dihydrobenzimidazole, 2-oxodihydrobenzo[d][1,3]oxazinyl, 2-oxo -3,4-dihydro-1H-quinazolinyl, 2-oxo-3,4-dihydro-1H-quinolinyl, 4-oxo-dihydroimidazolyl, 2-oxo-1, 3-Dihydroindolyl, 1-oxo-3H-isobenzofuryl, 2-oxo-1H-pyrido[2,3-b][1,4]oxazinyl, 2-oxo -1,3,4,5-tetrahydrobenzo[b]azepanyl, 2-oxotetrahydrobenzo[e][1,4]diazepanyl, 4-oxo Substitute-3H-thieno[2,3-d]pyrimidinyl, 5-oxo-4H-[1,2,4]triazinyl, C1-8 alkylenedioxy substituted phenyl, 2,3 -diazanaphthyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, 1H-pyrrolidinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3- c] pyridyl, pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, pyrrolyl, 1,3,4,5-tetrahydrobenzo[b]nitrogen Heterocycloheptenyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, thiazolyl, thienyl, triazinyl, triazolyl, 1,1,3-trioxodi Hydrogen-2H-1λ6-benzo[1,4]thiazinyl, [1,2,3]triazolo[1,5-a]pyridyl or [1,2,4]triazolo[4, 3-a] pyridyl.

The term saturated heterocyclyl denotes a 3-16 membered mono-, bi- or polycyclic saturated heterocyclyl having 1 to 4 nitrogen and/or 1 or 2 sulfur or oxygen atoms. Preference is given to 3-8-membered, particularly preferably 5- or 6-membered monocyclic groups which optionally have 3-8-membered fused rings which may be carbocyclic or heterocyclic. Further preferred heterocyclic groups are bi- or polycyclic heterocyclic rings optionally having spiro or bridged rings. Preferred heterocyclic groups have 1 nitrogen, oxygen or sulfur atom, 1-2 nitrogen atoms and 1-2 oxygen atoms or 1-2 nitrogen atoms and 1-2 sulfur atoms in each ring, wherein in At least one, preferably 1-7 carbon atoms are present in each ring.

Examples of saturated heterocyclyl groups are azepanyl, azetidinyl, aziridinyl, 3,4-dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl, 3,5-Dimethylmorpholinyl, Dioxanyl, [1,4]dioxepanyl, Dioxolanyl, 4,4-Di-Oxothiomorpholine Base, Dithianyl, Dithiolanyl, 2-Hydroxymethylpyrrolidinyl, 4-Hydroxypiperidinyl, 3-Hydroxypyrrolidinyl, 4-Methylpiperazinyl, 1-Methylpiperidinyl Base, 1-methylpyrrolidinyl, morpholinyl, oxathione, oxepanyl, 2-oxoazepanyl, 2-oxoimidazolidinyl, 2- Oxooxazolidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxotetrahydropyrimidinyl, 4-oxothiomorpholinyl, Piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrophenylthio, tetrahydrothiopyranyl, thiepanyl or thiomorpholinyl.

Examples of bi- or polycyclic heterocyclyl groups are 2,5-dioxabicyclo[4.1.0]heptyl, 2-oxa-bicyclo[2.2.1]heptyl, 2-oxabicyclo[4.1 .0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 2-oxabicyclo[3.1.0]hexyl, 3-oxo Heterobicyclo[3.1.0]hexyl, 1-oxaspiro[2.5]octyl, 6-oxaspiro[2.5]octyl, 3-oxabicyclo[3.3.1]nonyl, 2-oxo -1a,7b-dihydro-1H-cycloprop[c]benzopyranyl or 1,1a,2,7b-tetrahydrocyclopropane[c]benzopyranyl.

The heterocyclyl group can be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted or disubstituted, by the following groups: C _1-8 alkanoyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{1 -8} alkoxy, C _1-8 alkoxy-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxycarbonylamino, C _{1- 8} alkyl, C _0-8 alkylcarbonylamino, C _1-8 alkylcarbonyloxy, C _1-8 alkylenedioxy, optional N-mono or N, N-di-C _1-8 Alkylated amino, aryl, optionally N-mono- or N,N-di-C _1-8 alkylated carbamoyl, optionally esterified carboxy, cyano, C _3-8 cycloalkoxy, halogen , heteroaryl, heterocyclyl, hydroxyl, nitro, oxide, oxo, polyhalogenated C _1-8 alkoxy or polyhalogenated C _1-8 alkyl.

In the case of ^R , the aryl and heterocyclyl groups may also be further substituted by heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxyalkyl or heterocyclyl groups such as : Piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazine Subgroup (piperazino) alkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]-triazol-1-ylalkyl, [1,2,4] -Triazol-1-yl alkoxy, [1,2,4]-triazol-4-yl-alkyl, [1,2,4]-triazol-4-yl alkoxy, [1, 2,4]-oxadiazol-5-ylalkyl, [1,2,4]-oxadiazol-5-ylalkoxy, 3-methyl-[1,2,4]-oxadiazole -5-ylalkyl, 3-methyl-[1,2,4]-oxadiazol-5-ylalkoxy, 5-methyl-[1,2,4]-oxadiazol-3- ylalkyl, 5-methyl-[1,2,4]-oxadiazol-3-ylalkoxy, tetrazol-1-ylalkyl, tetrazol-1-ylalkoxy, tetrazole- 2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5-methyl-tetrazol-1-ylalkyl, 5 -Methyltetrazol-1-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2 -Oxopyrrolidinylalkyl, 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy, N-methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, and alkylaminoalkyl, alkylaminoalkoxy , Alkylaminoalkoxyalkyl, Mono- and polyhydroxyalkyl, Mono- and polyhydroxyalkoxy, Mono- and polyhydroxyalkoxyalkyl, Mono- and polyhydroxyalkoxyalkoxy, Carbamoylalkoxy Oxygen, C _1-8 alkoxy, amino-C _1-8 alkoxy, hydroxy-C _1-8 alkoxy, dioxolanyl, dioxanyl, dithiolanyl , Dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3- Hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-C _1-8 alkoxy-C _1-8 alkylpyrrolidinyl, 4-hydroxypiperidinyl Pyridyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-di Methylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo[1,3]oxazinyl, 2-oxo-tetra Hydropyrimidinyl, etc. or substituted by the group -O- _CH2CH (OH) _CH2NRx , where _NRx is mono- or di- _{C1-8alkylamino} , piperidino, morpholino _, piperazine subgroup or N-methylpiperazino group.

Halogen- and/or hydroxy-substituted C _1-8 alkoxy may be, for example, hydroxy-C 1-8 alkoxy or polyhydroxy-C _1-8 alkoxy.

The term polyhydroxyalkyl denotes a C _1-8 alkyl group which may be substituted by 2-8 hydroxyl groups, such as glyceryl, arabityl, sorbityl and the like. Similar statements apply to groups derived therefrom, such as polyhydroxy-C _1-8 alkoxy.

The compounds of formula (I) have at least three asymmetric carbon atoms and can therefore be obtained in the form of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, diastereomeric racemate mixtures Or exist in the form of mesogenic compounds. The present invention includes all such forms. Diastereomeric mixtures, diastereomeric racemates or diastereomeric racemate mixtures can be fractionated by conventional methods, eg column chromatography, thin chromatography, HPLC and the like.

Salts of compounds having salt-forming groups are in particular acid addition salts, salts with bases or, if several salt-forming groups are present, optionally also mixed or inner salts.

Salts are primarily pharmaceutically acceptable or non-toxic salts of compounds of formula (I).

Such salts are formed, for example, from compounds of formula (I) having acid groups, such as carboxyl or sulfo, and are, for example, their salts with suitable bases, such as those derived from groups Ia, Ib, IIa and 11b of the Periodic Table of the Elements Nontoxic metal salts of metals, such as alkali metals, especially lithium, sodium or potassium salts, alkaline earth metal salts, such as magnesium or calcium salts, and zinc or ammonium salts, also salts with organic amines, the organic amines For example optionally hydroxy-substituted mono-, di- or trialkylamines, especially mono-, di- or tri-lower alkylamines, or salts with quaternary ammonium bases such as methylamine, ethylamine, Diethylamine or triethylamine, mono-, di- or tri(2-hydroxy-lower alkyl)amines, for example ethanolamine, diethanolamine or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, N, N-di-lower alkyl-N-(hydroxy-lower alkyl)amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or N-methyl-D-glucamine, Or a quaternary ammonium hydroxide such as tetrabutylammonium hydroxide. Compounds of the formula I having a base such as amino can, for example, form acid addition salts with suitable inorganic acids, such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid with one or two protons replaced, Phosphoric acid with one or more protons replaced, such as orthophosphoric acid or metaphosphoric acid, or pyrophosphoric acid with one or more protons replaced, or acid-forming with organic carboxylic, sulfonic or phosphonic acids or N-substituted sulfamic acids Addition salts of organic carboxylic, sulfonic or phosphonic acids or N-substituted sulfamic acids such as acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylmaleic, Fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxy Benzoic acid, 2-acetoxybenzoic acid, pamoic acid, nicotinic acid, isonicotinic acid, and amino acids such as the alpha-amino acids mentioned above, and methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 1, 2-ethanedisulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglyceric acid, glucose-6-phosphate, N-cyclohexylsulfamic acid (forming ring hexanesulfonate), or form acid addition salts with other acidic organic compounds, such as ascorbic acid. Compounds of the formula (I) having acid groups and bases can also form inner salts.

Drug-mismatched salts can also be used for isolation and purification.

Preferred compounds of the invention are those of general formula (IA) and salts thereof, preferably pharmaceutically acceptable salts thereof:

wherein R ² , R ³ , W and X have the meanings given above for the compounds of formula (I).

Further preferred compounds of the formula (I), and particularly preferred compounds of the formula (IA) and salts thereof, preferably pharmaceutically acceptable salts thereof are compounds in which

R ¹ is a heterocyclic group substituted by oxo or oxide or a heterocyclic group represented by (B) or (C) below, wherein the heterocyclic group is particularly preferably selected from the group consisting of azepanyl, benzo[1, 3] Dioxolyl, benzofuranyl, benzimidazolyl, 4H-benzo[1,4]oxazinyl, benzoxazolyl, 4H-benzo[1,4]thiazolyl Azinyl, quinolinyl, benzopyranyl, dihydrobenzo[e][1,4]diazepanyl, dihydrobenzofuranyl, 3,4-dihydro-2H-benzene And[1,4]oxazinyl, dihydro-3H-benzo[1,4]oxazinyl, dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydro-2H -Benzo[1,4]thiazinyl, dihydro-2H-1λ6-benzo[1,4]thiazinyl, dihydro-1H-quinazolinyl, 1a,7b-dihydro-1H-cyclo Propan[c]benzopyranyl, dihydroimidazolyl, 1,3-dihydroindolyl, 2,3-dihydroindolyl, dihydro-1H-pyrido[2,3-b][ 1,4]oxazinyl, indazolyl, indolyl, 3H-isobenzofuryl, [1,5]diazinyl, oxazolyl, 2,3-diazinyl, piperidine Pyridyl, pyrazolyl, 1H-pyrido[2,3-b][1,4]oxazinyl, pyridyl, 1H-pyrrolidinyl, 1H-pyrrolo[2,3-b]pyridinyl, Pyrrolyl, tetrahydrobenzo[e][1,4]diazepanyl, 3H-thieno[2,3-d]pyrimidinyl, tetrahydroquinoxalinyl, 1,1a,2, 7b-tetrahydro-cyclopropane[c]benzopyranyl, tetrahydropyranyl or triazinyl.

Particularly preferred radicals ^R are azepanyl, benzo[1,3]dioxolyl, benzofuranyl, benzimidazolyl, 4H-benzo[1,4] Oxazinyl, Benzoxazolyl, 4H-Benzo[1,4]thiazinyl, Quinolinyl, Benzopyranyl, Dihydrobenzo[e][1,4]diazepanyl Alkenyl, dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, dihydro-3H-benzo[1,4]oxazinyl, dihydrobenzo [d][1,3]oxazinyl, 3,4-dihydro-2H-benzo[1,4]thiazinyl, dihydro-2H-1λ6-benzo[1,4]thiazinyl, Dihydro-1H-quinazolinyl, 1a,7b-dihydro-1H-cyclopropane[c]benzopyranyl, dihydroimidazolyl, 1,3-dihydroindolyl, 2,3-di Hydroindolyl, dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, indazolyl, indolyl, 3H-isobenzofuranyl, [1,5]di Azanaphthyl, oxazolyl, 2,3-diazinyl, piperidinyl, pyrazolyl, 1H-pyrido[2,3-b][1,4]oxazinyl, pyridinyl, 1H-pyrrolidinyl, 1H-pyrrolo[2,3-b]pyridyl, pyrrolyl, tetrahydrobenzo[e][1,4]diazepanyl, 3H-thieno[2, 3-d] pyrimidinyl, tetrahydroquinoxalinyl, 1,1a, 2,7b-tetrahydro-cyclopropane [c] benzopyranyl, tetrahydropyranyl or by 1-3 C _{1- 8} alkanoyl, C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkoxy-C _1-8 alkane Base, C _1-8 alkoxy-C _1-8 alkyl, (NC _1-8 alkoxy)-C _1-8 alkylaminocarbonyl-C _1-8 alkoxy, (NC _1-8 alkoxy Oxygen)-C _1-8 alkylaminocarbonyl-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkylcarbonyl, C _1-8 alkoxycarbonylamino-C _1-8 Alkoxy, C _1-8 alkoxycarbonylamino-C _{1-8 alkyl, C 1-8 alkyl} , (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 Alkoxy, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkyl, C _0-8 alkylcarbonylamino-C _1-8 alkoxy, C _0-8 Alkylcarbonylamino-C _1-8 alkyl, halogen, oxide, oxo, polyhalogenated C _1-8 alkoxy, polyhalogenated C _1-8 alkyl, [1,2,4]triazole -1-ylalkyl, [1,2,4]triazol-4-ylalkyl, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl or Thiazol-4-ylalkyl.

R ¹ is very particularly preferably composed of 1-3 C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkoxy -C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkylcarbonyl, C _1-8 alkoxycarbonylamino-C _1-8 alkoxy, C _1-8 alkoxycarbonylamino-C 1-8 alkyl _{, C 1-8 alkyl, (NC 1-8 alkyl )} -C _0-8 alkylcarbonylamino-C _1-8 alkoxy, (NC _1-8 alkyl)-C _0-8 alkylcarbonylamino-C _1-8 alkyl, C _0-8 alkylcarbonylamino-C _1-8 alkoxy, C _0-8 alkylcarbonylamino-C _1-8 alkyl, halogen, oxo, polyhalogenated-C _1-8 alkoxy or polyhalogenated-C _1-8 alkyl substituted benzopyranyl, 3,4-Dihydro-2H-benzo[1,4]oxazinyl, 3,4-dihydro-2H-benzo[1,4]thiazinyl or 1,3-dihydroindolyl.

Further preferred compounds of formula (I), or particularly preferred compounds of formula (IA) and salts thereof, preferably pharmaceutically acceptable salts thereof are various compounds, wherein

^R has the meaning represented by (A) or (B), particularly preferably the meaning represented by (A);

^R has the meaning represented by (a) or (b);

R ³ has the meaning represented by (a) or (b);

R ⁴ is C _1-8 alkyl or hydrogen;

R ⁵ is C _1-8 alkyl or hydrogen;

R ⁶ is C _1-8 alkyl or hydrogen;

X is -CHR ⁶ -Alk-R ¹ , -Alk-NR ⁴ -R ¹ , -Alk-OR ¹ , -Alk-SR ¹ , C _2-8 -alkenylene-R ¹ , -CH(OR ⁴ ) -Alk-R ¹ , -CHR ⁶ -Alk-R ¹ , -CHR ⁶ -OR ¹ , -CHR ⁶ -O-Alk-R ¹ , -CHR ⁶ -SR ¹ , -CHR ⁶ -S-Alk-R ¹ , -CO-Alk-R ¹ , -C(=NOR ⁵ )-Alk-R ¹ , -O-Alk-NR ⁴ -R ¹ , -O-Alk-R ¹ , -O-Alk-OR ¹ , - O-CO-R ¹ , -O-CO-Alk-R ¹ , -O-CHR ⁶ -R ¹ , -O-CHR ⁶ -Alk-R ¹ , -O-CHR ⁶ -CO-NR ⁴ -R ¹ or -O-CHR ⁶ -CO-NR ⁴ -Alk-R ¹ , wherein Alk is C _1-8 alkylene; and

W is -O-, -S- or cyano.

Further preferred compounds of formula (I), or particularly preferred compounds of formula (IA) and salts thereof, preferably pharmaceutically acceptable salts thereof are compounds in which

^R has the meaning represented by (A) or (B), particularly preferably the meaning represented by (A);

^R has the meaning represented by (a) or (b);

R ³ has the meaning represented by (a) or (b);

R ⁴ is C _1-8 alkyl or hydrogen;

R ⁵ is C _1-8 alkyl or hydrogen;

R ⁶ is C _1-8 alkyl or hydrogen;

X is -CHR ⁶ -Alk-R ¹ , -CH(OR ⁴ )-Alk-R ¹ , -O-Alk-R ¹ , -O-CHR ⁶ -R ¹ or -O-CHR ⁶ -CO-NR ⁴ -R ¹ , wherein Alk is C _1-8 alkylene; and

W is -O-, -S- or cyano.

Further preference is given to compounds of formula (I) and (IA) and their salts, preferably their pharmaceutically acceptable salts, wherein X is preferably -CHR ⁶ -Alk-R ¹ , -CH(OR ⁴ )-Alk-R ¹ , -O -Alk-R ¹ , -O-CHR ⁶ -R ¹ or -O-CHR ⁶ -CO-NR ⁴ -R ¹ .

Furthermore, preference is given to compounds of the formulas (I) and (IA) and their salts, preferably their pharmaceutically acceptable salts, wherein

R ³ a) is halogen- and/or hydroxy-substituted C _1-8 alkoxy, halogen- and/or hydroxy-substituted C _1-8 alkoxy-C _1-8 alkoxy, branched C _1-8 alkoxy-C _1-8 alkoxy, optional N-single or N, N-di-C _1-8 alkylated amino-C _1-8 alkoxy, optional N-single or N, N-di-C _1-8 alkylated amino-C _0-8 alkylcarbonyl-C _1-8 alkoxy, substituted C _3-8 cycloalkyl-C _0-8 alkoxy, any Select C _1-8 alkoxy or hydroxyl-substituted heterocyclyl-C _0-8 alkoxy, heterocyclylcarbonyl-C _0-8 alkoxy, heterocyclylcarbonyl-C _0-8 alkyl, Optionally halogen-substituted heterocyclyl-C _0-8 alkyl-carbonylamino-C _1-8 alkyl, optionally halogen-substituted C _3-8 cycloalkyl-C _0-8 alkylcarbonyl-amino-C _1-8 alkyl or optionally halogen substituted C _1-8 alkylcarbonylamino-C _1-8 alkyl; or additionally

b) If -WR ² is not C _1-8 alkoxy, then R ³ is hydroxyl, unsubstituted C _1-8 alkoxy, unsubstituted unbranched C _1-8 alkoxy-C _1-8 -alkoxy or unsubstituted C _3-8 cycloalkyl-C _0-8 alkoxy.

^R is very particularly preferably

a) Hydroxy-substituted C _1-8 alkoxy, optionally hydroxy-substituted C _1-8 alkoxy-C _1-8 alkoxy, branched C _1-8 alkoxy-C _1-8 Alkoxy or C _1-8 alkylcarbonylamino-C _1-8 alkyl; or additionally

b) If -WR ² is not C _1-8 alkoxy, then R ³ is hydroxyl, unsubstituted C _1-8 alkoxy or unsubstituted unbranched C _1-8 alkoxy-C _1-8 alkoxy.

Furthermore, preference is given to compounds of the formulas (I) and (IA) and their salts, preferably their pharmaceutically acceptable salts, wherein

R ² is C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkoxy-C 1-8 alkyl, C _1-8 alkoxy-C _3-8 cycloalkyl- _{C 1 -8} alkyl, C _3-8 cycloalkyl-C _0-8 alkoxy- _C 1-8 alkyl, C _1-8 alkylthio-C _1-8 alkyl, C _1-8 alkylsulfonate Acyl-C _1-8 alkyl;

R ³ is C _1-8 alkoxy substituted by hydroxy, C _1-8 alkoxy-C _1-8 alkoxy optionally substituted by hydroxy, hydroxyl or C _1-8 alkylcarbonylamino-C _1-8 alkyl; and

W-S-.

Furthermore, preference is given to compounds of the formulas (I) and (IA) and their salts, preferably their pharmaceutically acceptable salts, wherein

R ² is C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _3-8 cycloalkyl-C _{1 -8} alkyl, C _3-8 cycloalkyl-C _0-8 alkoxy- _C 1-8 alkyl, C _1-8 alkylthio-C _1-8 alkyl, C _1-8 alkylsulfonate Acyl-C _1-8 alkyl;

R ³ a) is hydroxyl-substituted C _1-8 alkoxy, hydroxyl-substituted C _1-8 alkoxy-C _1-8 alkoxy, branched C _1-8 alkoxy-C _{1- 8} alkoxy or C _1-8 alkylcarbonylamino-C _1-8 alkyl; or additionally

b) If R ² is not C _1-8 alkyl, then R ³ is hydroxyl, unsubstituted C _1-8 alkoxy or unsubstituted unbranched C _1-8 alkoxy-C _1-8 alkoxy base;

and

W is -O-.

When W is -O- or -S-, the particularly preferred group ^R2 is C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkoxy-C _1-8 alkyl, C _3-8 Cycloalkyl-C _0-8 Alkoxy-C _1-8 Alkyl, C _1-8 Alkylthio-C _1-8 Alkyl or C _1-8 Alkylsulfonyl-C _1-8 alkyl;

Very particular preference is given to compounds of the formulas (I) and (IA) and their salts, preferably their pharmaceutically acceptable salts, wherein

^R is substituted benzopyranyl or 3,4-dihydro-2H-benzo[1,4]oxazinyl;

R ² is C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _3-8 cycloalkyl-C _{1 -8} alkyl, C _3-8 cycloalkyl-C _0-8 alkoxy-C _1-8 alkyl, C _1-8 alkylthio-C _1-8 alkyl;

R ³ a) is hydroxyl-substituted C _1-8 alkoxy, hydroxyl-substituted C _1-8 alkoxy-C _1-8 alkoxy, branched C _1-8 alkoxy-C _{1- 8} alkoxy or C _1-8 alkylcarbonylamino-C _1-8 alkyl; or additionally

b) If R ² is not C _1-8 alkyl, then R ³ is hydroxyl, unsubstituted C _1-8 alkoxy or unsubstituted unbranched C _1-8 alkoxy-C _1-8 alkoxy base.

R ⁶ is C _1-8 alkyl or hydrogen;

X is -CHR ⁶ -Alk-R ¹ or -O-Alk-R ¹ , wherein Alk is C _1-8 alkylene; and

W is -O-.

The radicals of the above compounds are not considered to be closed; rather, some of the radicals of these compounds may be interchanged or substituted in a suitable manner by the given definitions or preferences, or omitted, e.g. by more specific definitions comprehensively substitute. The definitions and preferences stated apply within the scope of general chemical principles, such as the usual valences of atoms.

Compounds of formula (I) can be prepared in a manner analogous to the preparation methods disclosed in the literature. Similar preparations are described, for example, in WO 97/09311. Details of specific preparation variations can be found in the Examples.

Compounds of formula (I) can also be prepared in optically pure form. The separation of the enantiomers can be carried out by methods known per se, preferably early in the synthesis by formation of salts with optically active acids, such as (+)- or (-)-mandelic acid, and separation of the diastereomeric salts by fractional crystallization, Or preferably after derivatization with a chiral auxiliary component, such as (+)- or (-)-camphoryl chloride, and separation by chromatography and/or crystallization and subsequent bond cleavage of the chiral auxiliary A later stage of the projected product. To determine the absolute configuration of the piperidines contained, the pure diastereomeric salts and derivatives can be analyzed by conventional spectroscopic methods, of which X-ray spectroscopy based on single crystals is a particularly suitable method.

Compounds of formula (I) and (IA) also include compounds in which one or more atoms are replaced by their stable non-radioactive isotopes; for example a hydrogen atom is replaced by deuterium.

Prodrug derivatives of the compounds described herein are derivatives thereof that release the original compound when used in vivo as a result of chemical or physiological processes. Prodrugs can be converted, for example, into the starting compound when physiological pH is reached or as a result of enzymatic conversion. Suitable examples of prodrug derivatives are esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, acyl being as defined above. Preferred derivatives are pharmaceutically acceptable ester derivatives which are converted to the original carboxylic acid by solvolysis in physiological media, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono Or disubstituted lower alkyl esters, for example lower ω-(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl)-alkyl esters or for example lower α-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)-alkyl esters; pivaloyloxymethyl and similar esters are generally used as such.

Because of the close relationship between free compounds, prodrug derivatives and salt compounds, it is appropriate and appropriate that particular compounds in the present invention also include their prodrug derivatives and salt forms. The definitions apply within the scope of general chemical principles, such as the usual valences of atoms.

Compounds of formula (I) or (IA) and their pharmaceutically acceptable salts have an inhibitory effect on the natural enzyme renin. The latter enters the blood through the kidneys, where it causes the dissociation of angiotensinogen to form the decapeptide angiotensin I, which is then broken down in the lungs, kidneys and other organs to the octapeptide angiotensin II. Angiotensin II raises blood pressure directly through arterial constriction and indirectly through the release of the hormone aldosterone from the adrenal gland, which retains sodium ions associated with increased extracellular fluid volume. This increase can be attributed to the influence of angiotensin II itself or the heptapeptide angiotensin III formed therefrom as a dissociation product. Inhibitors of reninase activity cause a reduction in the formation of angiotensin I, and thus in small amounts, of angiotensin II. The decrease in the concentration of this active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.

The effect of renin inhibitors was examined in particular experimentally by in vitro tests in which the reduction of angiotensin I formation was measured in various systems (human plasma, purified human renin together with synthetic or natural renin substrates). In particular the following in vitro test of Nussberger et al. (1987), J. Cardiovascular Pharmacol., Vol. 9, pp. 39-44 was used. This test measures the formation of angiotensin I in human plasma. The amount of angiotensin I formed was determined in a subsequent radioimmunoassay. The effect of the inhibitors on the formation of angiotensin I was tested in this system by adding various concentrations of these substances. _IC50 is defined as the concentration of a particular inhibitor that reduces the formation of angiotensin I by 50%. The compounds of the present invention show inhibitory effects in in vitro systems at a minimum concentration of about 10 ^-6 to about 10 ^-10 mol/l. According to the description of the present invention, the compounds of Examples 1, 2, 5, 8, 61, 68, 70, 71, 73, 74, 87 and 91 inhibit the formation of angiotensin I with _IC50 values of about 3.8-814· 10 ^-9 mol/l.

The hypotensive effect of the compounds described herein can be tested in vivo by the following protocol:

The studies were performed in 5- to 6-week-old male double transgenic rats (dTGR) exhibiting human angiotensinogen and human renin and thus developing hypertension. This double transgenic rat strain was generated by crossing two breeds, a first transgene for human angiotensinogen with an endogenous enhancer and a second transgene with an endogenous enhancer for human renin. Neither genetically modified variety had previously been hypertensive. The double transgenic rats, both male and female, developed severe hypertension (mean systolic arterial blood pressure of approximately 200 mm Hg) and survived a median of 55 days. The fact that human renin can be studied in rats is a hallmark of this model. Age-appropriate Sprague-Dawley rats were used as non-hypertensive control animals. Animals are divided into treatment groups and receive active compound, comparison substance or vehicle (control) daily for several weeks. Doses for oral administration may range from 0.5 to 100 mg/kg body weight. Animals received standard chow and ad libitum drinking water throughout the study period. By implanting sensors in the abdominal aorta, systolic and diastolic blood pressure and heart rate were measured telemetrically, and the animals were able to move freely and unrestricted.

The effect of the compounds described herein on renal impairment (proteinuria) can be tested in vivo by the following protocol:

Studies were performed in 4 week male double transgenic rats (dTGR) as described above. Animals are divided into treatment groups and receive active compound, comparison substance or vehicle (control) for 7 weeks. Doses for oral administration may range from 0.5 to 100 mg/kg body weight. Animals received standard chow and ad libitum drinking water throughout the study period. Animals are placed periodically in metabolic cages for the determination of 24-hour albumin excretion, diuresis, natriuresis, and urine osmolarity in urine. At the end of the study, the animals are sacrificed and kidneys and hearts can be removed for weight measurements and immunohistological studies (fibrosis, macrophage/T cell invasion, etc.).

Renin inhibitors cause a drop in blood pressure in animals that consume salt. Human renin is different from other species of renin. Inhibitors of human renin were tested using primates (marmoset, Callithrix jacchus), since human renin and primate renin are substantially homologous in the region of enzymatic activity. Specifically the following in vivo test was used: the test compounds were tested on normotensive marmosets of both sexes weighing about 350 g, conscious, unrestrained and in their normal cages. Blood pressure and heart rate were measured and radioactively recorded using a catheter in the descending aorta. By combining a low-salt diet with a single intramuscular injection of celiac acid (5-(aminosulfonyl)-4-chloro-2-[(2-furylmethyl)amino]benzoic acid) (5 mg/kg) for 1 week , to stimulate the endogenous release of renin. 16 hours after the injection of celiac, the test substances were administered directly into the femoral artery via a hypodermic needle, or the test substances were administered as a suspension or solution into the stomach by gavage, and their effects on blood pressure and heart rate were evaluated . The compounds of the present invention have a hypotensive effect in said in vivo test with an in vivo dose of about 0.003 to about 0.3 mg/kg and an oral dose of about 0.3 to about 30 mg/kg.

The pharmacokinetic properties of the compounds described herein can be tested in vivo by the following protocol:

The study was performed in pre-catheterized (carotid artery) male rats (300 g ± 20%) capable of unlimited mobility throughout the procedure. Compounds are administered intravenously and orally (gavage) to individual animals. The dose for oral administration may be 0.5 to 50 mg/kg body weight; the dose for intravenous administration may be 0.5 to 20 mg/kg body weight. Blood samples were drawn automatically via the catheter by means of AccuSampler (DiLab Europe, Lund, Sweden) before and during the subsequent 24 hours of compound administration. Plasma levels of compounds are then measured using validated LC-MS assays. Subsequently, pharmacokinetic analysis was performed based on plasma concentration-time curves after measuring mean concentrations at various time points. The analysis included the following parameters: maximum concentration ( _Cmax ), time to reach maximum concentration ( _tmax ), area under the curve (AUC _0-t ) for time from 0 hours to last quantifiable concentration, curve for time from 0 hours to infinity Area under (AUC _0-infinity ), elimination constant (K), terminal half-life (t _1/2 ), absolute oral bioavailability (F), clearance (CL) and volume of distribution during terminal phase (Vd).

The compounds of formula (I) and preferably formula (IA) and their pharmaceutically acceptable salts can be used as medicaments, eg in the form of pharmaceutical products. The pharmaceutical product can be administered internally, e.g. orally, e.g. nasally, e.g. in the form of a nasal spray, e.g. in the form of tablets, lacquered tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration, eg, rectally, in the form of suppositories, or transdermally, eg, in the form of ointments or patches. However, parenteral administration, for example in the form of injectable solutions, eg intramuscularly or intravenously, is equally suitable.

Tablets, coated tablets, dragees and hard gelatin capsules can be produced by processing a compound of formula (I), or preferably formula (IA), and pharmaceutically acceptable salts thereof, with pharmaceutically inert inorganic or organic excipients . Excipients of these types which may be used, for example, in tablets, dragees and hard gelatin capsules are lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, and the like.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Excipients suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, dextrose and the like.

Excipients suitable for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin and the like.

Excipients suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical product may additionally contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coatings or antioxidants . They may also include other therapeutically valuable substances.

The present invention further provides formula (I), or the compound of preferred formula (IA) and pharmaceutically acceptable salt thereof in the treatment or prevention of hypertension, heart failure, glaucoma, myocardial infarction, renal failure, restenosis (restenoses) and stroke use.

The compounds of formula (I) and preferably formula (IA) and their pharmaceutically acceptable salts can also be administered in combination with one or more agents having cardiovascular activity, such as alpha- and beta-blockers, for example Phentolamine, phenoxybenzamine, prazosin, terazosin, 2-methylphenazine (tolazine), atenolol, metoprolol, nadolol, propranol Vasodilators, such as hydralazine, minoxidil, diazoxide, nitroprusside, flusquinan, etc.; calcium antagonists, such as Amrinone, bencyclan, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexiline, verapamil, golopamil, nifedipine, etc. ACE inhibitors, such as cilazapril, captopril, enalapril, lisinopril, etc.; potassium activators, such as pinacidil; antiserotoninergics, such as ketones (ketanserine); thromboxane synthase inhibitors; neutral endopeptidase inhibitors (NEP inhibitors); angiotensin II antagonists; and diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride , bumetanide, benzthiazide, ethacrynic acid, furosemide, indalidone, metolazone, spironolactone, triamterene, chlorthalidone, etc.; sympathetic blockers, such as methyldopa, clonidine, guanabenz, reserpine; and others indicated for the treatment of hypertension, heart failure or vascular disease associated with diabetes or nephropathy such as acute or chronic renal failure in humans and animals Drugs for diseases. This combination can be used independently or in the form of a product comprising a plurality of components.

Other substances which may be used in combination with compounds of formula (I), (IA) and pharmaceutically acceptable salts thereof are compounds of classes (i) to (ix) on page 1 of WO 02/40007 (and the preferred compounds further detailed therein. and Examples) and the substances described on pages 20 and 21 of WO 03/027091.

The present invention therefore further provides a pharmaceutical combination in the form of a product or in the form of a kit consisting of individual components consisting of a) a compound of general formula (I) according to any one of claims 1 to 6 or Pharmaceutically acceptable salts thereof, and b) constituted as at least one pharmaceutical form of the active ingredient with cardiovascular action.

The dosage may vary widely and must unquestionably be adapted to the individual situation in each individual case. Generally, a daily dose suitable for oral administration should be from about 3 mg to about 3 g, preferably from about 10 mg to about 1 g, for example about 300 mg per adult (70 kg), divided into preferably 1-3 individual doses which may be For example equal amounts, but if this is indicated to be justified, the upper limit may also be exceeded and young children will generally receive reduced doses appropriate for their age and weight.

Example

The following examples illustrate the invention. All temperatures are expressed in degrees Celsius and pressures in millibars. Unless mentioned otherwise, reactions were carried out at room temperature. The abbreviation "Rf=xx(A)" indicates that Rf xx is found in solvent system A, for example. The ratios of solvent amounts to one another are always expressed as volume ratios. The chemical names of final products and intermediates were generated with the aid of the AutoNom 2000 (AutomaticNomenclature) program.

Mobile phase systems for thin layer chromatography:

A dichloromethane-methanol-25% concentrated ammonia water=200:20:1

B dichloromethane-methanol-25% concentrated ammonia water=200:20:0.5

C dichloromethane-methanol-25% concentrated ammonia water=200:10:1

D dichloromethane-methanol-25% concentrated ammonia water=90:10:1

E dichloromethane-methanol-25% concentrated ammonia water=60:10:1

F dichloromethane-methanol-25% concentrated ammonia water=200:30:1

G dichloromethane-methanol＝9:1

H dichloromethane-methanol-25% concentrated ammonia water=200:40:1

1 dichloromethane-methanol-25% concentrated ammonia water=100:10:1

J dichloromethane-methanol=20:1

K dichloromethane-methanol-25% concentrated ammonia water=40:10:1

HPLC gradient on Hypersil BDS C-18 (5 μm); column: 4 x 125 mm

(I) 90% water ^* /10% acetonitrile ^* to 0% water ^* /100% acetonitrile ^* 5 minutes + 2.5 minutes (1.5ml/min)

(II) 95% water ^* /5% acetonitrile ^* to 0% water ^* /100% acetonitrile ^* for 40 minutes (0.8ml/min)

HPLC gradient on Zorbax SB-C18 (3.5 μm); column: 2.1 x 30mm

(III) 97.5% water ^* /2.5% acetonitrile ^* to 5% water ^* /95% acetonitrile ^* 5.5 minutes + 2.4 minutes (0.5ml/min)

^* Contains 0.1% trifluoroacetic acid

Use the following abbreviations:

Rf The ratio of the distance a substance migrates to the distance from the solvent front to the starting point in thin-layer chromatography

Rt The residence time of the substance in HPLC (in minutes)

M.p. melting point (temperature)

General Method A: (N-BOC Deprotection)

15 ml of methanol and 2.5 ml of 2N HCl were successively added to a 1 mmol "N-BOC derivative" solution in 5 ml of chloroform, and the mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, poured into 1M aqueous sodium bicarbonate (40ml) and extracted with tert-butyl methyl ether (2 x 60ml). The organic phase was washed with brine (1 x 60ml), dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Method B: (Hydrogenation)

15 ml of a 1 mmol "substrate" solution in 1:1 tetrahydrofuran/methanol was hydrogenated in the presence of 100-200 mg of 10% Pd/C at 15-20 °C for 2-20 hours. The reaction mixture was purified by filtration and the filtrate was evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General method C: (9-BBN reduction)

A solution of 1 mmol "lactam" in 3 ml THF was mixed with 3.2-6.4 mmol 9-BBN (0.5M in THF) and stirred at reflux for 1-2 hours (conversion checked by HPLC). The reaction mixture was cooled to room temperature and evaporated after addition of 3.2-6.4 mmol ethanolamine. The residue was stirred in 1:1 ethyl acetate/heptane (30ml) at 0°C overnight and clarified by filtration, and the filtrate was evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Method D: (O-Alkylation)

Add 1.1 mmol of sodium hydride (60% dispersion in oil) to 1 mmol of "alcohol", 1.0-2.0 mmol of "benzyl" in 2.0 ml of N,N-dimethylformamide with stirring at -10°C Halogen". The reaction mixture was stirred at -10°C for 1 hour and at room temperature for 18 hours. The mixture was poured into 1M aqueous sodium bicarbonate (50ml) and extracted with tert-butyl methyl ether (2 x 50ml). The organic phase was washed successively with water (1 x 50ml) and brine (1 x 60ml), dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Method E: (chlorination)

A solution of 6.40 ml of pyridine and 40 mmol of "benzyl alcohol" in 100 ml of dichloromethane was slowly added dropwise to a solution of 7.65 ml of thionyl chloride in 20 ml of dichloromethane previously cooled to 0-5 °C. The reaction mixture was each stirred for 1 hour at 0° C. and then at room temperature and then poured into 200 ml of ice-water. The mixture was extracted with dichloromethane (2 x 200ml). The organic phase was washed successively with 1M aqueous sodium bicarbonate (2 x 200ml) and brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure F: (Phenol Alkylation I)

20 mmol of "phenol" in 60 ml of N,N-dimethylformamide was stirred with 4.15 g of potassium carbonate and 30 mmol of "halide" or "tosylate" at 100°C for 24 hours. The reaction mixture was then evaporated. The residue was mixed with 1M aqueous sodium bicarbonate (40ml) and extracted with ethyl acetate (2 x 60ml). The organic phase was washed with brine (1 x 60ml), dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure G: (Phenol Alkylation II)

A suspension of 1 mmol of "tosylate", 2 mmol of "phenol", 2 mmol of potassium carbonate and 20 ml of acetonitrile was stirred at 90°C for 24 hours. The reaction mixture was then evaporated. The residue was mixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2x). The organic phase was washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure H: (Tosylation)

12mmol of p-toluenesulfonyl chloride solution in 15ml of dichloromethane was added dropwise to a solution of 10mmol of "alcohol", 15mmol of triethylamine, and 1mmol of 4-dimethylaminopyridine in 90ml of dichloromethane at 0°C. The reaction mixture was stirred at room temperature for 2-18 hours. The reaction mixture was diluted with dichloromethane then washed with water and brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure I: (Phenol Alkylation III)

A suspension of 1 mmol "phenol", 1.0-1.5 mmol "tosylate" or "bromide", 1.5 mmol cesium carbonate and 2 ml acetonitrile was stirred at 80°C for 2 hours. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2x). The organic phase was washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure J (Alcohol Desilylation)

A solution of 1 mmol "silyl ether" in 5 ml tetrahydrofuran was mixed with 1.5-2.0 mmol tetrabutylammonium fluoride (1M solution in tetrahydrofuran) and the solution was stirred at room temperature for 1-2 hours. The reaction solution was then diluted with water and extracted 2 times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure K (Borane Reduction)

A 1 mmol "lactam" solution in 3 ml THF was mixed with 3.0-6.0 mmol borane-THF complex (1 M in THF) and stirred at room temperature for 1-3 hours (conversion checked by HPLC or TLC). The reaction mixture was cooled to room temperature, mixed with 3.0-6.0 mmol methanol and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure L (N-Tos Deprotection I)

0.44 mmol of sodium dihydrogen phosphate and 0.90 mmol of sodium amalgam (10% Na) were added successively to a solution of 0.09 mmol of "toluenesulfonamide" in 10 ml of methanol at room temperature. The reaction mixture was stirred for 2-18 hours, diluted with water and extracted with ethyl acetate. The organic phase was separated and washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure M (O-Alkylation II)

1 mmol of methylmagnesium bromide (35% solution in diethyl ether) was added to a solution of 1 mmol of "secondary alcohol" in 5 ml of tetrahydrofuran at room temperature. The reaction solution was heated to reflux for 5 minutes, then a solution of 2.2 mmol "ethylene oxide" in 1 ml THF was added. The reaction mixture was heated to reflux for 1-5 hours, poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

General Procedure N (N-Tos Deprotection II)

Add 0.5 ml of blue-green sodium naphthyl sodium stock solution (0.04 g sodium and 0.22 g naphthalene from 5 ml dimethoxyethane) to 0.1 mmol "toluenesulfonamide" in 2 ml dimethoxyethane at -60 °C " in solution. After 3-6 hours, the reaction mixture was diluted with water and extracted with dichloromethane (2x). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

Example 1

{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzene And[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}acetonitrile

From 0.185g of [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzene The title compound was prepared analogously to Method L and [1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetonitrile.

The starting materials were prepared as follows:

a) [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-1-(toluene 4-sulfonyl)piperidin-3-yloxy]acetonitrile

0.164 g of sodium hydride (60% dispersion in oil) was added to 0.50 g of (3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-ol Stir the solution. The reaction mixture was stirred at room temperature for 1 hour. 0.762 g of bromoacetonitrile was added at -20°C, and the mixture was stirred at -20°C for 48 hours. The reaction mixture was poured into 1M aqueous sodium bicarbonate (30ml) and extracted with tert-butyl methyl ether (2 x 100ml). The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.30 (EtOAc-heptane 1:1); Rt = 5.13 (gradient I).

b) (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1 , 4] oxazin-6-ylmethoxy]-1-(toluene 4-sulfonyl)piperidin-3-ol

At room temperature, 14.74 g of tetrabutylammonium fluoride trihydrate was added to 23.2 g of 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene -4-sulfonyl)-5-triisopropylsilyloxypiperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzene And [1,4] oxazine solution. After 1 hour 10 ml of water were added to the reaction mixture and the mixture was evaporated to dryness. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.06 (EtOAc-heptane 1:2); Rt = 4.73 (gradient I).

c) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-triisopropylsilyloxypiperidine- 3- oxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4] oxazine

24.99 g of 6-[(3R,4R,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-triisopropylsilane were prepared analogously to method C Oxypiperidin-3-yloxymethyl]-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one reaction. The title compound was obtained as a colorless resin. Rf = 0.10 (EtOAc-heptane 1:2).

d) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-triisopropylsilyloxypiperidine- 3- oxymethyl]-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one

19.0 g of (3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-triisopropylsilyloxypiperide were prepared analogously to method D Pyridin-3-ol was reacted with 11.52 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one. The title compound was obtained as a pale yellow resin. Rf = 0.18 (EtOAc-heptane 1:2); Rt = 6.67 (gradient 1).

e) (3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5- triisopropylsilyloxypiperidin - 3-ol

At 80°C, 55.64g (3R, 4R, 5S)-4-(4-hydroxyphenyl)-1-(toluene-4-sulfonyl)-5-triisopropylsilyloxypiperidin-3-ol A suspension of 15.0 g dimethyl sulfate, 20.92 g potassium carbonate and 750 ml acetone was stirred for 24 hours. The reaction mixture was purified by filtration and evaporated. The residue was diluted with 1.75 l of tert-butylmethyl ether and 1 l of water was added. The aqueous phase was extracted again with 11 tert-butyl methyl ether. The combined organic phases were washed with 750 ml brine, dried over sodium sulfate and evaporated. The crude title compound was obtained from the residue as a white foam. Rt = 6.27 (gradient I).

f) (3R, 4R, 5S)-4-(4-hydroxyphenyl)-1-(toluene-4-sulfonyl)-5- triisopropylsilyloxypiperidin - 3-ol

Add 26.08 g of toluenesulfonyl chloride to 50 g of (3R, 4R, 5S)-4-(4-hydroxyphenyl)-5-triisopropylsilyloxy in 11 ethyl acetate and 112N sodium carbonate solution at 0°C in a mixture of piperidin-3-ols. After 4 hours at 0°C, the reaction mixture was stirred at room temperature for an additional 16 hours. The phases were separated and the aqueous phase was extracted with 200 ml ethyl acetate. The combined organic phases were washed with 200 ml of brine, dried over sodium sulfate and evaporated. The title compound was obtained in the form of white crystals. Rf = 0.31 (EtOAc-heptane 1:1.5); Rt = 5.77 (gradient 1).

g) (3R, 4R, 5S)-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidin-3-ol

5.210 g of (3R,4R,5S)-4-(4-benzyloxyphenyl)-1-((R)-1-phenylethyl)-5-triisopropyl silyloxy-piperidin-3-ol reaction. The title compound was obtained as a colorless solid. Rf=0.19 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=3.80 (gradient I).

h) (3R, 4R, 5S)-4-(4-benzyloxyphenyl)-1-((R)-1-phenylethyl)-5- triisopropylsilyloxypiperidine- 3-ol

Add 150ml of borane-tetrahydrofuran complex (1M in tetrahydrofuran) dropwise to 20.00g of (S)-4-(4-benzyloxy) in 280ml of 1,2-dimethoxyethane at 0°C Phenyl)-1-((R)-1-phenylethyl)-3-triisopropylsilyloxy-1,2,3,4-tetrahydropyridine solution. The reaction solution was then stirred at 30°C for 3 hours. The solution was cooled to room temperature and quenched with 70 ml of water. After stirring for 5 minutes, 56.00 g of sodium percarbonate were added and the suspension was stirred at 50° C. for 1 hour. The reaction mixture was poured into 600 ml of water and extracted with ethyl acetate (2x). The combined organic phases were washed with 400 ml each of water and brine and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.23 (EtOAc-heptane 1:2); Rt = 5.75 (gradient I).

i) (S)-4-(4-benzyloxyphenyl)-1-((R)-1-phenylethyl)-3- triisopropylsilyloxy -1,2,3, 6-tetrahydropiperidine

6.80ml of 2,6-lutidine was added to 14.70g of 4-(4-benzyloxyphenyl)-1-(1(R)-phenylethyl)- 1,2,3,6-tetrahydropyridin-3(S)-ol [257928-45-3] in suspension. 12.60 ml of triisopropylsilyl trifluoromethanesulfonate were added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into 400 ml of water and the phases were separated. The aqueous phase was back-extracted with 200 ml of dichloromethane, and the combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained from the residue as a yellow-brown oil by flash chromatography ( _SiO2 60F). Rf = 0.66 (EtOAc-heptane 1:2); Rt = 5.83 (gradient I).

j) 6-Chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one

0.37 g of 6-hydroxymethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one were reacted analogously to method E. The title compound was obtained as a colorless oil. Rf = 0.60 (EtOAc-heptane 2:1); Rt = 4.05 (gradient 1).

k) 6-Hydroxymethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one

Mix 1.79g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one, 2.20ml of 1-chloro-3-methoxypropane, 10g of potassium fluoride on alumina and 150ml A suspension of 0.033 g potassium iodide in acetonitrile was stirred at reflux for 72 hours. The reaction mixture was cooled and clarified by filtration, and the filtrate was evaporated to dryness. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.60 (dichloromethane-methanol 9:1); Rt = 2.74 (gradient I).

m) 6-Hydroxymethyl-4H-benzo[1,4]oxazin-3-one

A mixture of 6.9 g of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylate [202195-67-3] and 230 ml of tetrahydrofuran was cooled to -40 °C . 88.9 ml of diisobutylaluminum hydride (1.5M in toluene) were added dropwise over 30 minutes at -40°C. The reaction mixture was stirred at -40°C to -20°C for 1.5 hours, then poured carefully into 150 ml of 2N HCl (cold). The organic phase was separated and the aqueous phase was extracted with tetrahydrofuran (5 x 100ml). The organic phase was washed with brine (1 x 100ml), filtered through cotton wool and evaporated. The title compound is obtained from the residue by crystallization (from ethanol) in the form of beige crystals. Rf = 0.16 (EtOAc-heptane 2:1); Rt = 2.23 (gradient I); m.p.: 186-187°C.

Example 2

(R)-1-methoxy-3-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-2-ol

From 0.282 g of (R)-1-methoxy-3-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yl Oxy]-propan-2-ol to prepare the title compound.

The starting materials were prepared as follows:

a) (R)-1-methoxy-3-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3- yloxy]propane-2- alcohol

0.30 g of (3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro S-(+ )-glycidyl methyl ether [64491-68-5] reaction. The title compound was obtained as a colorless oil. Rf = 0.19 (EtOAc-heptane 2:1); Rt = 4.81 (gradient 1).

The following compounds were prepared in a manner analogous to the method described in Example 2:

Example 3

(S)-1-methoxy-3-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-2-ol

Use R-(-)-glycidyl methyl ether [64491-70-9]

Example 5

6-[(3R,4R,5S)-4-(4-methoxyphenyl)-5-prop-2-ynyloxypiperidin-3-yloxymethyl Base]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine

0.236 g of sodium dihydrogen phosphate and 0.743 g of sodium amalgam (sodium amalgan) (10% Na) were continuously added to 0.209 g of 6-[(3R, 4R, 5S)-4-( 4-methoxyphenyl)-5-prop-2-ynyloxy-1-(toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazine solution. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 20 hours. The mixture was decanted and filtered through Hyflo. The filtrate was evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-prop-2-ynyloxy-1-(toluene-4- sulfonyl )piperidine-3 -yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

0.263 g of sodium hydride (60% dispersion in oil) was added to 1.50 g of (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3 -Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidine-3- Alcohol (Example 1b) and 1.099 g of 3-bromopropyne solution. After stirring for 22 hours, the reaction mixture was mixed with 40 ml saturated sodium bicarbonate solution and extracted with tert-butyl methyl ether (3 x 50 ml). The combined organic phases were washed with 40 ml brine, dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.18 (EtOAc-heptane 1:2); Rt = 5.26 (gradient I).

Example 6

6-[(3R,4R,5S)-4-(4-methoxyphenyl)-5-(4-morpholin-4-yl-but-2-ynyloxy)piperidine -3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

0.194 g of sodium dihydrogen phosphate and 0.612 g of sodium amalgam (sodium amalgan) (10% Na) were continuously added to 0.199 g of 6-[(3R, 4R, 5S)-4-( 4-methoxyphenyl)-5-(4-morpholin-4-ylbut-2-ynyloxy)-1-(toluene-4-sulfonyl)piperidin-3-yloxymethyl] -4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine solution. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature for 24 hours. The mixture was decanted and filtered through Hyflo. The filtrate was evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-(4-morpholin-4-yl-but-2- ynyloxy )-1-( Toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1,4]oxazine

A suspension of 0.038 g of paraformaldehyde and 0.032 g of morpholine in 4 ml of dioxane was heated until the solution became clear and then stirred at room temperature for 20 minutes. 0.21 g of 6-[(3R,4R,5S)-4-(4-methoxyphenyl)-5-prop-2-ynyloxy-1-(toluene-4 -sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine (Example 5a) and 0.068 g of copper(II) acetate solution were added to the solution. After 18 hours at 90°C, the reaction mixture was diluted with tert-butyl methyl ether, washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.19 (EtOAc-heptane 2:1); Rt = 4.55 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 6:

Example 7

(4-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-but-2-ynyl)dimethylamine

Example 8

6-[(3R,4R,5S)-5-(2-methoxy-2-methylpropoxy)-4-(4-methoxyphenyl)piperidine-3- Oxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.20 g of 6-[(3R,4R,5S)-5-(2-methoxy-2-methylpropoxy)-4-(4-methoxyphenyl)- 1-(Toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Oxyzine to prepare the title compound.

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-5-(2-methoxy-2-methylpropoxy)-4-(4- methoxyphenyl )-1-(toluene-4- Sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

Add 0.03 g of sodium hydride (60% dispersion in oil) to 0.20 g of 1-[(3S,4R,5R)-4-(4-methanol in 1.5 ml of N,N-dimethylformamide Oxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1- (Toluene-4-sulfonyl)piperidin-3-yloxy]-2-methylpropan-2-ol in a stirred solution. After 45 minutes at room temperature, 0.129 g of methyl iodide was added to the mixture. After 3 hours at room temperature, the reaction mixture was diluted with tert-butyl methyl ether. The solution was washed successively with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rt = 5.56 (gradient I).

b) 1-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-2-methylpropan-2- ol

A solution of 0.558 ml of methylmagnesium bromide (3N in ether) was added to 0.23 g of [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[ 4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piper Pyridin-3-yloxy]acetic acid methyl ester solution. After 15 minutes at 50°C, the reaction mixture was cooled to room temperature and diluted with 50 ml tert-butyl methyl ether. The solution was washed successively with 20 ml of saturated aqueous sodium bicarbonate and 10 ml of brine. The combined aqueous phases were extracted with 50 ml tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained from the residue as a white resin. Rt = 5.16 (gradient I).

c) [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]methyl acetate

With stirring, 0.085 g of sodium hydride (60% dispersion in oil) was added to 0.513 g of (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4- (3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidine- 3-alcohol (Example 1b) solution. The reaction mixture was stirred at room temperature for 1 hour, then 0.40 g of methyl bromoacetate was added at -20°C. After 1 hour at -20°C and 3 hours at room temperature, the reaction mixture was diluted with 100 ml tert-butyl methyl ether and washed with saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was extracted with tert-butyl methyl ether (2 x 50ml). The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.14 (EtOAc-heptane 1:2); Rt = 5.21 (gradient I).

Example 9

1-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-2-methylpropan-2-ol

From 0.125 g of 1-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-2-methylpropane- 2-Alcohol (Example 8b) Preparation of the title compound.

The following compounds were prepared in a manner analogous to the method described in Example 9:

Example 10

3-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxymethyl}pentan-3-ol

Example 11

(R)-1-methoxy-3-[(3S,4R,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]-4-(4-propoxyphenyl)piperidin-3-yloxy]propan-2-ol

From 0.303 g of (3S,4R,5R)-4-(4-allyloxyphenyl)-3-((R)-2-hydroxy-3-methoxypropoxy) analogously to method B -5-[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl Esters to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-4-(4-allyloxyphenyl)-3-((R)-2-hydroxy-3- methoxypropoxy )-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 1.400 g of (3S,4S,5R)-4-(4-allyloxyphenyl)-3-hydroxyl-5-[4-(3-methoxypropyl)-3 , 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester and 0.460g S-(+)-glycidyl methyl ether [64491 -68-5] The title compound was obtained in the form of a colorless oil. Rf = 0.34 (EtOAc-heptane 3:1); Rt = 5.06 (gradient 1).

b) (3S, 4S, 5R)-4-(4-allyloxyphenyl)-3-hydroxy-5-[4-(3- methoxypropyl )-3,4-dihydro-2H -Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

From 1.860 g of (3R,4R,5S)-4-(4-allyloxyphenyl)-3-[4-(3-methoxypropyl)-3,4-di Benzyl hydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate affords the title compound as a colorless resin. Rf = 0.18 (EtOAc-heptane 1:1); Rt = 4.97 (gradient 1).

c) (3R, 4R, 5S)-4-(4-allyloxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate benzyl ester

Add 0.820 g of potassium carbonate and 0.300 ml of allyl bromide to 2.090 g of (3R, 4R, 5S)-4-(4-hydroxyphenyl) in 5 ml of N,N-dimethylformamide at room temperature -3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy-5-triisopropylsilyloxy in the benzyl piperidine-1-carboxylate solution. The reaction mixture was stirred at 40-60°C for 5 hours, poured into a saturated aqueous solution of sodium bicarbonate, and extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.42 (EtOAc-heptane 1:1).

d) (3R, 4R, 5S)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4 ]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate benzyl ester

From 5.010 g of (3R,4R,5S)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4 in analogy to method K -Benzyldihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate affords the title compound as a light red resin . Rf = 0.32 (EtOAc-heptane 1:1); Rt = 29.32 (gradient II).

e) (3R, 4R, 5S)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate benzyl ester

1.620 g of tetraphenylphosphine palladium (0) and 7.300 g of potassium carbonate were added to 13.88 g of (3R, 4R, 5S)-4-(4-allyloxyphenyl)-3-[4 -(3-Methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilane Oxypiperidine-1-carboxylic acid benzyl ester solution. The reaction mixture was then stirred at room temperature for 3 hours. The solid was filtered off and the filtrate was evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.23 (EtOAc-heptane 1:1); Rt = 6.37 (gradient I).

f) (3R, 4R, 5S)-4-(4-allyloxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo- 3,4-dihydro- 2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1- carboxylate

From 16.50 g of (3R,4R,5S)-4-(4-allyloxyphenyl)-3-hydroxyl-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzene in a similar manner to method D The methyl ester afforded the title compound as a yellow resin. Rf = 0.18 (EtOAc-heptane 1:2); Rt = 7.07 (gradient 1).

g) Benzyl (3R,4R,5S)-4-(4-allyloxyphenyl)-3-hydroxy-5-triisopropylsilyloxypiperidine -1-carboxylate

16.66 g of benzyl (3R,4R,5S)-3-hydroxy-4-(4-hydroxy)-5-triisopropylsilyloxypiperidine-1-carboxylate were reacted analogously to method 11c. The title compound was obtained as a light brown resin. Rf = 0.42 (EtOAc-heptane 1:1); Rt = 6.54 (gradient 1).

h) Benzyl (3R, 4R, 5S)-3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine-1- carboxylate

20.07 ml of benzyl chloroformate was slowly added to 50 g of (3R, 4R, 5S)-4-(4-hydroxyphenyl)-5-tris in 1000 ml of saturated sodium bicarbonate solution and 1000 ml of ethyl acetate at 0°C. in a biphasic mixture of isopropylsiloxypiperidin-3-ol (Example 1g). After 3 hours at 0° C. and 15 hours at room temperature, the aqueous phase was separated and extracted with 200 ml of ethyl acetate. The combined organic phases were washed with 200 ml of brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.31 (EtOAc-heptane 1:1.5); Rt = 5.77 (gradient I).

Example 12

(R)-1-3-{(3S,4R,5R)-4-(4-allyloxyphenyl)-5-[4-(3-methoxypropyl)-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-3-methoxypropan-2-ol

5 ml of potassium hydroxide 40% aqueous solution was added to 0.375 g of (3S, 4R, 5R)-4-(4-allyloxyphenyl)-3-( (R)-2-hydroxy-3-methoxypropoxy)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Benzylazin-6-ylmethoxy]piperidine-1-carboxylate (Example 11a). The mixture was heated at 80°C for 5 hours in a closed flask. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

Example 13

(R)-1-[(3S,4R,5R)-4-(4-ethoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy]-3-methoxypropan-2-ol

From 0.600 g of (3S,4R,5R)-4-(4-ethoxyphenyl)-3-((R)-2-hydroxy-3-methoxypropoxy)-5 in analogy to method B Preparation of -[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-4-(4-ethoxyphenyl)-3-((R)-2-hydroxy-3- methoxypropoxy )-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 0.800 g of (3S,4S,5R)-4-(4-ethoxyphenyl)-3-hydroxyl-5-[4-(3-methoxypropyl)-3,4 -Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.268 g of S-(+)-glycidyl methyl ether gave light yellow The title compound as a resin. Rf = 0.24 (EtOAc-heptane 3:1); Rt = 4.98 (gradient 1).

b) (3S, 4S, 5R)-4-(4-ethoxyphenyl)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4- dihydro -2H- benzene And[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester

From 2.100 g of (3R,4R,5S)-4-(4-ethoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro- Benzyl 2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate affords the title compound in the form of a yellow resin. Rf = 0.27 (EtOAc-heptane 2:1); Rt = 4.88 (gradient 1).

c) (3R, 4R, 5S)-4-(4-ethoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1, 4] Oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate benzyl ester

Add 0.185 g of sodium hydride (60% dispersion in oil) to 2.500 g of (3R,4R,5S)-4-(4-hydroxybenzene) in 35 ml of N,N-dimethylformamide at 0 °C Base)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropyl silyloxypiperidine-1-carboxylic acid benzyl ester (Example 11d) and 0.56 ml ethyl iodide solution. The reaction mixture was stirred at room temperature for 3 hours, poured into saturated aqueous sodium bicarbonate and extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue as a yellow resin by flash chromatography ( _SiO2 60F). Rf = 0.23 (EtOAc-heptane 1:2).

Example 14

4-{(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-2-methylbutan-2-ol

From 0.044 g of 4-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-2-methylbutan- 2-Alcohol Preparation of the title compound.

The starting materials were prepared as follows:

a) 4-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-2- methylbutan -2- ol

0.046 g of 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3 was prepared analogously to Example 8b, 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]propanoic acid methyl ester and 0.109 ml of methylmagnesium bromide solution (3N in ether). The title compound was obtained as a colorless resin. Rt = 5.11 (gradient I).

b) 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene Methyl [1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy] propionate

Add 0.043g of methyl acrylate to 0.10g of (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl) in 0.5ml of acetonitrile -3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-ol (Example 1b) and 0.013g of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) solution. After 18 hours at 45°C, 0.043 g of methyl acrylate was added to the reaction solution again. After 24 hours, the reaction mixture was evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.47 (EtOAc-heptane 2:1); Rt = 5.23 (gradient I).

Example 16

3-{(3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-1-ol

From 0.088 g of 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-yloxy]-propan-1-ol Preparation of the title compound.

The starting materials were prepared as follows:

a) 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]propan-1- ol

0.389 g of 6-[(3R,4S,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(3-triiso Propylsilyloxypropoxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa oxine reaction. The title compound was obtained as a colorless resin. Rf = 0.36 (EtOAc-heptane 4:1); Rt = 4.80 (gradient 1).

b) 6-[(3R,4S,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(3- triisopropylsilyloxypropoxy Base) piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

0.043 g of sodium hydride (60% dispersion in oil) was added to 0.50 g of (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3 -Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidine-3- Alcohol (Example 1b), 0.268g of (3-bromopropoxy)triisopropylsilane [215650-24-1] and 0.009g of tetrabutylammonium iodide solution. After 15 hours at 50° C., the reaction mixture was diluted with 200 ml tert-butyl methyl ether at room temperature. The solution was washed successively with 30 ml aqueous sodium bicarbonate, 30 ml water and 20 ml brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.31 (EtOAc-heptane 1:2).

Example 17

6-[(3R,4S,5S)-4-(4-methoxyphenyl)-5-(3-[1,2,4]triazol-1-yl-propoxy)piperidine -3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.150 g of 6-[(3R,4S,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(3-[1 ,2,4]triazol-1-yl-propoxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzene and[1,4]oxazine to prepare the title compound.

The starting materials were prepared as follows:

a) 6-[(3R,4S,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(3-[1,2,4] triazole -1-yl-propoxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxa Zinc

0.115 g of 1,2,4-triazole sodium salt [41253-21-8] was added to 0.184 g of 3-[(3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6 -ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]propyltoluene-4-sulfonate solution. After 15 hours at room temperature, the reaction mixture was diluted with 100 ml ethyl acetate and washed successively with 15 ml saturated aqueous sodium bicarbonate and 15 ml brine. The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.10 (EtOAc-heptane 4:1); Rt = 4.72 (gradient I).

b) 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene A[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy] propyltoluene - 4-sulfonate

From 0.195 g of 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-yloxy]-propan-1-ol (Example 16a) The title compound was obtained in the form of a colorless oil. Rf = 0.22 (EtOAc-heptane 1:1); Rt = 5.68 (gradient 1).

Example 18

(R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(2-methoxyethoxy)phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-2- alcohol

From 0.200 g of (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-4-[4-(2-methoxyethyl) in a similar manner to method B Oxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-Benzyl carboxylate to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-4-[4-(2- methoxyethoxy )phenyl]- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

From 0.580 g of (3S,4S,5R)-3-hydroxy-4-[4-(2-methoxyethoxy)phenyl]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester and 0.185 g of S-(+)- Glycidyl methyl ether [64491-68-5] gave the title compound as a colorless oil. Rf = 0.15 (EtOAc-heptane 2:1); Rt = 4.70 (gradient 1).

b) (3S, 4S, 5R)-3-hydroxy-4-[4-(2-methoxyethoxy)phenyl]-5-[4-(3-methoxypropyl )-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

From 0.584 g of (3R,4R,5R)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H in a similar manner to method I -Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-benzoic acid benzyl ester (Example 11d) and 0.334 g of 2-methoxy Ethyltoluene-4-sulfonate [17178-10-8] gave the title compound as a colorless oil. Rf = 0.20 (EtOAc-heptane 2:1); Rt = 4.62 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 18:

Example

142(R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-((S)-4-methoxy-3-methyl-butoxy Base)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]- piperidin-3-yloxy}-propan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-((S)-4-methoxy-3-methyl-butoxy)-phenyl]-5-[4-(3 -Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 140a )start.

143 (S)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-((S)-4-methoxy-3-methyl- butoxy )-phenyl ]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy] -piperidine-3- oxy)-propan-2-ol

Using R-(-)-glycidyl methyl ether [64491-70-9] from (3S, 4S, 5R)-3-hydroxy-4-[4-((S)-4-methoxy-3 -Methyl-butoxy)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6- Benzylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 140a)

147 (R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-pentyloxy) -phenyl ]-5-[ 4-(3-Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin -3-yloxy}- propan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-((R)-4-methoxy-pentyloxy)-phenyl]-5-[4-(3-methoxy- Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 145a)

148 (S)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-pentyloxy) -phenyl ]-5-[ 4-(3-Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin -3-yloxy}- propan-2-ol

Using R-(-)-glycidyl methyl ether [64491-70-9] from (3S,4S,5R)-3-hydroxy-4-[4-((R)-4-methoxy-pentane Oxy)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy] -benzyl piperidine-1-carboxylate (Example 145a) started

Example 19

(R)-3-{(3S,4R,5R)-4-[4-(2-methoxyethoxy)phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-1,2-diol

From 0.225 g of (3S,4R,5R)-3-((R)-2,3-dihydroxy-propoxy)-4-(4-methoxyphenyl)-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate Preparation title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2,3-dihydroxypropoxy)-4-(4- methoxyphenyl )-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 4.600 g of (3S, 4R, 5R)-3-[(S)-3-(tert-butyldimethylsilyloxy)-2-hydroxypropoxy]-4-(4) in analogy to method J -Methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piper Benzyl pyridine-1-carboxylate afforded the title compound as a yellow oil. Rf = 0.11 (EtOAc-heptane 3:1); Rt = 4.38 (gradient 1).

b) (3S, 4R, 5R)-3-[(S)-3-(tert-butyldimethylsilyloxy)-2- hydroxypropoxy ]-4-(4-methoxyphenyl) -5-[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy]piperidine-1-carboxylic acid benzyl ester

From 2.210 g of (3S,4S,5R)-3-hydroxy-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3 in analogy to method M, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester and 1.86ml of tert-butyldimethyl ((S)-1- Oxiranylmethoxy)silane [123237-62-7] gave the title compound as a light brown oil. Rt = 6.14 (gradient I).

c) (3S, 4S, 5R)-3-hydroxy-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester

From 26.59 g of (3R,4R,5S)-3-hydroxy-4-(4-methoxyphenyl)-5-triisopropyl Benzyl siloxypiperidine-1-carboxylate afforded the title compound as a pale yellow oil. Rf = 0.25 (EtOAc-heptane 3:1); Rt = 4.69 (gradient I).

d) (3R, 4R, 5S)-3-Hydroxy-4-(4-methoxyphenyl)-5-triisopropylsilyloxypiperidine- 1-carboxylic acid benzyl ester

From 25 g of benzyl (3R,4R,5S)-3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylate in analogy to Example 1e The title compound as a pale yellow resin. Rt = 6.35 (gradient I).

Example 20

(R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-prop-2- alcohol

From 0.260 g of (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-4-[4-(3-methoxypropoxy) in analogy to method B Oxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-Benzyl carboxylate to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-4-[4-(3- methoxypropoxy ) phenyl]- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

From 0.580 g of (3S,4R,5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxy Benzylpropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester afforded the title compound as a pale yellow resin. Rf = 0.15 (EtOAc-heptane 3:1); Rt = 4.92 (gradient 1).

b) (3S, 4S, 5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl )-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

From 39.10 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl) in analogy to method J -Benzyl 3,4-di-hydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate to give a yellow oil form of the title compound. Rf = 0.17 (EtOAc-heptane 4:1); Rt = 4.80 (gradient 1).

c) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro Benzyl-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1- carboxylate

From 40.75 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl) analogously to method K -3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl Esters afforded the title compound as a pale yellow oil. Rf = 0.51 (EtOAc-heptane 1:1).

d) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3-oxo-3 , Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine- 1-carboxylate

From 33.45 g of (3R, 4R, 5S)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-triisopropylsilyloxypiper in analogy to method D Benzyl pyridine-1-carboxylate afforded the title compound as a pale yellow oil. Rf = 0.40 (EtOAc-heptane 1:1); Rt = 7.05 (gradient 1).

e) (3R, 4R, 5S)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5- triisopropylsilyloxypiperidine - 1-carboxylic acid benzene methyl ester

From 32.00 g of benzyl (3R,4R,5S)-3-hydroxy-4-[4-hydroxyphenyl]-5-triisopropylsilyloxypiperidine-1-carboxylate in analogy to method F The title compound as a colorless oil. Rf = 0.28 (EtOAc-heptane 1:2); Rt = 6.48 (gradient 1).

Example 21

1-methoxy-3-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-2-one

From 0.123 g of (3S, 4R, 5R)-3-(3-methoxy-2-oxo-propoxy)-4-(4-methoxyphenyl)-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate Preparation title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-(3-methoxy-2-oxopropoxy)-4-(4- methoxyphenyl )-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

Add 1.00ml of triethylamine dropwise into 0.820g of (3S, 4R, 5R)-3-((R)-( 2-Hydroxy-3-methoxypropoxy)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-formic acid benzyl ester solution.Add 0.981g of sulfur trioxide-pyridine complex, and stir the reaction solution at room temperature for 16 Hour. The reaction solution was poured into ice-water, adjusted to pH 2-3 with 1M aqueous potassium bisulfate solution, and extracted with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. By flash chromatography ( _SiO2 60F) from the residue gives the title compound as a pale yellow oil. Rf = 0.26 (EtOAc-heptane 2:1); Rt = 4.97 (gradient I).

b) (3S, 4R, 5R)-3-((R)-(2-hydroxy-3-methoxypropoxy)-4-(4- methoxyphenyl )-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 1.570 g of (3S,4S,5R)-3-hydroxy-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3 in analogy to method M, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 19c) and S-(+)-glycidyl of 0.181 Methyl ether [64491-68-5] gave the title compound as a colorless oil. Rf = 0.19 (EtOAc-heptane 2:1); Rt = 4.77 (gradient 1).

Example 22

6-[(3R,4R,5S)-5-(2-Methanesulfonylethoxy)-4-(4-methoxyphenyl)piperidin-3-yl Oxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.48 g of 6-[(3R,4R,5S)-5-(2-methanesulfonylethoxy)-4-(4-methoxyphenyl)-1-(toluene- 4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine Preparation of the title compound .

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-5-(2-methanesulfonylethoxy)-4-(4-methoxyphenyl)-1-( toluene -4- sulfonyl)- Piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

0.472 g of (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-ol (Example 1b) and 0.834 g of methylethylene Base sulfone [3680-02-2] reaction. The title compound was obtained as a pale yellow oil. Rf = 0.35 (EtOAc-heptane 2:1); Rt = 4.91 (gradient 1).

Example 23

4-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxymethyl}tetrahydropyran-4-ol

From 0.270 g of 4-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxymethyl]tetrahydropyran- 4-Alcohol Preparation of the title compound.

The starting materials were prepared as follows:

a) 4-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxymethyl] tetrahydropyran - 4-ol

Add 0.04 g of sodium hydride (60% dispersion in oil) to 0.40 of 6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (3S, 4S, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4] Oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-ol (Example 1b) in solution. The mixture was stirred at 60° C. for 10 minutes, then a solution of 0.174 g of 1,6-dioxaspiro[2.5]octane[185-72-8] in 2 ml of DMPU was added. After 1 hour at 60° C., the reaction mixture was cooled at room temperature and diluted with 200 ml tert-butyl methyl ether. The solution was washed successively with 20 ml of 1N HCl, 30 ml of unsaturated aqueous sodium bicarbonate and 20 ml of brine. The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.23 (EtOAc-heptane 2:1); Rt = 4.87 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 23:

Example

137 6-[(3R, 4R, 5S)-5-[1-(2-methoxy-ethoxy)-cyclopentylmethoxy]-4-(4- methoxy -phenyl)- Piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo [1,4]oxazine

Using 1-iodomethyl-1-(2-methoxy-ethoxy)-cyclopentane

The starting materials were prepared as follows:

a) 1-iodomethyl-1-(2-methoxy-ethoxy)-cyclopentane

To a solution of 25.98 mmol of 2-methoxyethanol [109-86-4] and 23.62 mmol of methylenecyclopentane [1528-30-9] in dry acrylonitrile (actetinitile) was added 25.98 mmol of N-iodosuccinimide. The reaction mixture was stirred at room temperature in the dark for 20 hours. The reaction mixture was poured into brine, extracted with ether (2x) and evaporated to concentrate. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.42 (EtOAc-heptane 1:4).

Example 24

2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-N,N-dimethylacetamide

From 0.140 g of 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-N,N-dimethyl Acetamide to prepare the title compound.

The starting materials were prepared as follows:

a) 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-N,N- dimethylacetamide

0.145 g of [(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxyphenyl) Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy Base] methyl acetate (Example 8c) for 24 hours, then evaporated to dryness. The title compound is obtained from the residue in the form of a yellow oil. Rt = 4.82 (gradient I).

Example 25

(R, S)-1-methoxy-3-{(3S,4R,5R)-4-(4-methoxyphenyl-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy-2-methylpropan-2- alcohol

From 0.381 g of (3S, 4R, 5R)-3-((R, S)-2-hydroxy-3-methoxy-2-methylpropoxy)-4-(4- Methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-Benzyl carboxylate to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R, S)-2-hydroxy-3-methoxy-2-methylpropoxy)-4-(4-methoxyphenyl )- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

Add 0.30 ml of methylmagnesium bromide solution (35% in diethyl ether) to 0.542 g of (3S,4R,5R)-3-(3-methoxy-2-oxopropane) in 5 ml of dry THF at room temperature Oxy)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine- 6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 21a) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1M aqueous potassium hydrogensulfate solution and extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography (SiO2 60F). Rf = 0.15 (EtOAc-heptane 2:1); Rt = 5.03 (gradient 1).

Example 26

(R)-2-fluoro-3-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}propan-1-ol

Add 0.10 ml of 2M aqueous HCl to 0.135 g of (3S,4R,5R)-3((R)-3-benzyloxy-2-fluoropropoxy)- 4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl Oxy]piperidine-1-carboxylic acid benzyl ester solution, and hydrogenation was carried out at 20° C. in the presence of 60 mg of 10% Pd/C for 6 hours. The reaction mixture was purified by filtration through Hyflo and the filtrate was evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3((R)-3-benzyloxy-2-fluoropropoxy)-4-(4- methoxyphenyl )-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

A solution of 0.081 ml of diethylaminosulfur trifluoride in 5 ml of dry dichloromethane was cooled to -78°C. At this temperature, 0.418 g of (3S, 4R, 5R)-3((S)-3-benzyloxy-2-hydroxy-propoxy)-4-(4-methanol) in 5 ml of dichloromethane was added dropwise. Oxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine- 1-Benzyl formate solution. The reaction solution was stirred at -78°C for 1 hour and then allowed to warm to room temperature over 3-4 hours. The reaction mixture was poured into a mixture of ice and saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and evaporated. The title compound is obtained in the form of a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.29 (EtOAc-heptane 1:1); Rt = 5.70 (gradient I).

b) (3S, 4R, 5R)-3((S)-3-benzyloxy-2-hydroxypropoxy)-4-(4- methoxyphenyl )-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 0.406 g of (3S,4S,5R)-3-hydroxy-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3 in analogy to method M, 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 19c) and 0.257 of (R)-2-benzyloxy Propylene oxide [14618-80-5] gave the title compound as a yellow oil. Rf = 0.38 (EtOAc-heptane 3:1); Rt = 5.33 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 26:

Example 27

(S)-2-fluoro-3-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy]propan-1-ol

Example 28

2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-pyrrolidin-1-yl-ethanone

From 0.29 g of 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-1-pyrrolidin-1 -yl-ethanone to prepare the title compound.

The starting materials were prepared as follows:

a) 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]-1-pyrrolidin- 1-yl-ethanone

At 75°C, 0.37 g of [(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- Solution of methyl 2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetate and 0.39 g of pyrrolidine Heat for 2 hours. The solvent was evaporated in vacuo and the title compound was obtained as white crystals from the residue by flash chromatography ( _SiO2 60F). Rf = 0.22 (EtOAc-heptane 3:1); Rt = 4.94 (gradient I).

b) 3-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetate methyl ester

0.53 g of sodium hydride (60% dispersion in oil) was added to 3.2 g of ((3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidine-3 -alcohol (Example 1b) solution, and the mixture was stirred at room temperature for 1 hour. It was then cooled to -5° C., and 2.49 g of methyl bromoacetate were added dropwise over 1 hour. The reaction mixture 3 was stirred at -5° C. hours and then warmed to room temperature. It was then diluted with tert-butyl methyl ether and poured into 0.5M aqueous HCl. The resulting mixture was extracted three times with tert-butyl methyl ether. The combined organic phases were washed with brine, dried over sodium sulfate, and evaporated. Flash chromatography ( _SiO2 60F) affords the title compound as a yellow oil from the residue. Rf = 0.5 (EtOAc-heptane 2:1); Rt = 5.14 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 28:

Example

32 2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-N-(tetrahydropyran-4-yl) acetamide

34 2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-morpholin-4-yl-ethanone

Example 29

(S)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-prop-2- alcohol

From 0.495 g of (3S, 4R, 5R)-3-((S)-2-hydroxy-3-methoxypropoxy)-4-[4-(3-methoxypropoxy) in analogy to method B Oxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-Benzyl carboxylate to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((S)-2-hydroxy-3-methoxypropoxy)-4-[4-(3- methoxypropoxy ) phenyl]- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

0.635 g of (3S,4S,5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) and 0.202 g of R -(-)-glycidyl methyl ether [64491-70-9] reaction. The title compound is obtained as a yellow oil. Rf = 0.06 (EtOAc-heptane 1:1); Rt = 4.91 (gradient 1).

Example 30

6-[(3R, 4S, 5S)-4-(4-methoxyphenyl)-5-(3-morpholin-4-yl-propoxy)piperidin-3-yloxy Methyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.26 g of 6-[(3R,4S,5S)-4-(4-methoxyphenyl)-5-(3-morpholin-4-yl-propoxy)-1 in analogy to method L -(Toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Oxyzine to prepare the title compound.

The starting materials were prepared as follows:

a) 6-[(3R, 4S, 5S)-4-(4-methoxyphenyl)-5-(3-morpholin-4-yl-propoxy)-1-( toluene -4- Sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

0.034ml of acetic acid, 0.054ml of morpholine and 0.181g of sodium triacetoxyborohydride were continuously added to 0.35g of 3-[(3S,4S,5R)-4-(4-methoxybenzene in 3.5ml of tetrahydrofuran Base)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene- 4-sulfonyl)piperidin-3-yloxy]propanal solution. After 1 hour at room temperature, the reaction mixture was poured into 30 ml ice-water and extracted with tert-butyl methyl ether (2 x 30 ml). The combined organic phases were washed successively with 30 ml of water and 30 ml of brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless resin from the residue by flash chromatography ( _SiO2 60F). Rf=0.33 (dichloromethane-methanol-25% concentrated ammonia water=200:10:1); Rt=4.46 (gradient I).

b) 3-[(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]propanal

0.328 g of pyridine-sulfur trioxide complex was added to 0.405 g of 3-[(3S, 4S, 5R)-4-(4 -Methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]- In a solution of 1-(toluene-4-sulfonyl)piperidin-3-yloxy]-propan-1-ol (Example 16a) and 0.433 ml triethylamine. After 3 hours at 0°C, the reaction mixture was stirred at room temperature. After 1 hour, a further 0.1 g of pyridine-sulfur trioxide complex was added. After an additional 1 hour, the reaction mixture was poured into 10 ml of ice-water, adjusted to pH 2.5 with 0.5 ml of 1N potassium bisulfate solution, and extracted with diethyl ether (3 x 20 ml). The combined organic phases were washed successively with 20 ml of water and 20 ml of 5% aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The crude title compound is obtained from the residue as a pale yellow resin. Rf = 0.09 (EtOAc-heptane 1:2); Rt = 5.04 (gradient 1).

Example 31

6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-(2-morpholin-4-ylethoxy)piperidin-3-yloxy Methyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.11 g of 6-[(3R,4R,5S)-4-(4-methoxyphenyl)-5-(2-morpholin-4-ylethoxy)-1- (Toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine Preparation of the title compound.

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-(2-morpholin-4-yl-ethoxy)-1-( toluene -4- Sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

0.122 g of [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetaldehyde and 0.0154 g of morpholine reaction. The title compound was obtained as a pale yellow resin. Rf=0.38 (dichloromethane-methanol-25% concentrated ammonia water=200:10:1); Rt=4.45 (gradient I).

b) [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetaldehyde

0.135 g of 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3 was prepared analogously to Example 30b, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]ethanol reaction. The title compound was obtained as a pale yellow resin. Rf = 0.05 (EtOAc-heptane 1:2); Rt = 4.67 (gradient 1).

c) 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]ethanol

0.19 g of 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(2-tri Isopropylsilyloxyethoxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4] Oxazine reaction. The title compound was obtained as a pale yellow resin. Rf = 0.31 (EtOAc-heptane 1:2); Rt = 4.77 (gradient 1).

d) 6-[(3R,4R,5S)-4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-5-(2- triisopropylsilyloxyethoxy Base) piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1,4]oxazine

0.044 g of sodium hydride (60% dispersion in oil) was added to 0.50 g of (3S,4S,5R)-4-(4-methoxyphenyl)-5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) Piperidin-3-ol (Example 1b) and 0.303 g of (2-iodoethoxy)triisopropylsilane [93550-77-7] solution. After 4 hours at 50° C., 0.303 g of (2-iodoethoxy)triisopropylsilane and 0.044 g of sodium hydride (60% dispersion in oil) were added to the mixture again. After 15 hours at 50°C, the reaction mixture was diluted with tert-butyl methyl ether at room temperature. The solution was washed successively with aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, and evaporated. The title compound is obtained as a light yellow resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.25 (EtOAc-heptane 1:2).

Example 33

6-{(3R, 4S, 5S)-5-(3-methoxypropoxy)-4-[4-(3-methoxypropoxy)phenyl]piperidine -3-yloxymethyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.218 g of (3S,4S,5R)-3-(-3-methoxypropoxy)-4-[4-(3-methoxypropoxy)phenyl]- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate The title compound was obtained.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-(3-methoxypropoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

Add 0.090 g of sodium hydride (60% dispersion in oil) to 0.955 g of (3S,4S,5R)-3-hydroxy- 4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4] Oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) in solution. The reaction mixture was stirred at 0 °C for 1 hour. 0.258 g of 1-bromo-3-methoxypropane and 0.023 g of sodium iodide were continuously added to the mixture. The reaction mixture was stirred at room temperature for 16 hours, then poured into 50 ml of water and extracted with tert-butyl methyl ether (3 x 50 ml). The organic phase was washed successively with water (2 x 50ml) and brine (50ml), dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.23 (EtOAc-heptane 3:1); Rt = 5.45 (gradient I).

Example 35

3-{(3S, 4S, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-1-ol

From 0.300 g of (3S, 4S, 5R)-3-(-3-hydroxypropoxy)-4-[4-(3-methoxypropoxy)phenyl]-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate yields the title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-(3-hydroxypropoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

2.95 g of (3R,4S,5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl) -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(3-triisopropylsilyloxypropoxy)piperidine-1-carboxylic acid Benzyl ester reaction. The title compound was obtained as a colorless oil. Rf = 0.11 (EtOAc-heptane 2:1); Rt = 4.83 (gradient 1).

b) (3R, 4S, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(3- triisopropylsilyloxypropoxy )piperidine-1-carboxylate

4.0 g of (3S, 4S, 5R)-3-hydroxyl-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methyl) was prepared similarly to Example 31d Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) and 2.07 g of (3-bromopropoxy)triisopropylsilane reaction. The title compound was obtained as a colorless oil. Rf = 0.56 (EtOAc-heptane 2:1).

Example 36

(R)-1-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-2-ol

From 0.340 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3-methoxypropyl) in analogy to method B )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1-oxiranylmethoxy)piperidine- Benzyl 1-carboxylate afforded the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1-oxiranylmethoxy)piperidine -1-carboxylate

Add 0.065 g of sodium hydride (60% dispersion in oil) to 0.860 g of (3S,4S,5R)-hydroxy-4-[4-(3-methoxypropoxy)benzene in 5 ml of THF Base]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid Benzyl ester (Example 20b) in solution. The mixture was stirred at 40°C for 45 minutes. A solution of 0.625 g of (R)-1-oxiranylmethyltoluene-4-sulfonate [113826-06-5] in 3 ml of tetrahydrofuran was added and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.25 (EtOAc-heptane 2:1); Rt = 5.26 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 36:

Example

44 (S)-1-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3- methoxypropyl ) -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-2-ol

From (3S, 4S, 5R)-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-di Benzyl hydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 20b) and 0.622 g of (S)-1-oxiranyl Methyltoluene-4-sulfonate [70987-78-9] started.

140 (R)-1-{(3S, 4R, 5R)-4-[4-((S)-4-methoxy-3-methyl-butoxy) -phenyl ]-5-[4 -(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}-prop- 2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-((S)-4-methoxy-3-methyl-butoxy)-phenyl]-5-[4-(3 -Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester to start.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-hydroxyl-4-[4-((S)-4-methoxy-3-methyl-butoxy) -phenyl ]-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1- carboxylic acid benzyl ester

(3R,4R , 5S)-Benzyl 3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylate (Example 11h) afforded the title compound. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

141 (S)-1-{(3S, 4R, 5R)-4-[4-((S)-4-methoxy-3-methyl-butoxy) -phenyl ]-5-[4 -(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}-prop- 2-ol

Using (S)-1-oxiranylmethyl ester [70987-78-9], from (3S,4S,5R)-3-hydroxy-4-[4-((S)-4-methoxy -3-Methyl-butoxy)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine- 6-Ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 140a) started.

145 (R)-1-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-pentyloxy)-phenyl]-5-[4-(3-methyl Oxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-2- ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-((R)-4-methoxy-pentyloxy)-phenyl]-5-[4-(3-methoxy- Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-hydroxy-4-[4-((R)-4-methoxy-pentyloxy)-phenyl]-5-[4-(3- methoxy -Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester

(3R,4R,5S)- Benzyl 3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylate (Example 11h) afforded the title compound. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

146 (S)-1-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-3-methyl-butoxy) -phenyl ]-5-[4 -(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}-prop- 2-ol

Using (S)-1-oxiranylmethyl ester [70987-78-9], from (3S,4S,5R)-3-hydroxy-4-[4-((R)-4-methoxy -pentyloxy)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy Benzyl]-piperidine-1-carboxylic acid benzyl ester (Example 145a).

Example 37

(3-{(3S, 4S, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propyl)dimethyl amine

From 0.190 g of (3S,4S,5R)-3-(3-dimethylamino-propoxy)-4-[4-(3-methoxypropoxy)phenyl] analogously to method B -5-[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl Esters afford the title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-(3-dimethylaminopropoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-(3 -Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

0.048 ml of acetic acid, 0.08 g of dimethylamine (in 0.5 ml of tetrahydrofuran) and 0.181 g of sodium triacetoxyborohydride were successively added to 0.530 g of (3R, 4S, 5S)- 4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4] Oxazin-6-ylmethoxy]-5-(3-oxopropoxy)piperidine-1-carboxylic acid benzyl ester solution. The reaction mixture was stirred at room temperature for 2 hours, then poured into 1M sodium bicarbonate solution (30ml) and extracted with tert-butyl methyl ether (2 x 30ml). The organic phase was washed successively with water (30ml) and brine (30ml), dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf=0.22 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=4.50 (gradient I).

b) (3R, 4S, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(3-oxopropoxy)piperidine-1-carboxylic acid benzyl ester

Partially add 0.46 g of pyridine-sulfur trioxide to 0.600 g of (3S,4S,5R)-3-(3-hydroxypropoxy )-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1, 4] Oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 35a) in solution. The reaction mixture was stirred at 0°C for 30 minutes and then poured into ice-water (10ml). 1M potassium bisulfite solution (0.5ml) was added to the mixture, which was then extracted with ether (3 x 20ml). The organic phase was washed successively with water (30ml) and 0.5M sodium bicarbonate solution (20ml), dried over sodium sulfate and evaporated. The crude title compound was obtained as a pale yellow oil. Rt = 5.14 (gradient I).

Example 38

6-[(3R,4S,5S)-4-[4-(3-methoxypropoxy)phenyl]-5-(3-[1,2,4]triazol-1-ylpropane Oxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.390 g of (3R,4S,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3-methoxypropyl) in analogy to method B )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(3-[1,2,4]triazol-1-ylpropoxy ) benzyl piperidine-1-carboxylate to give the title compound.

The starting materials were prepared as follows:

a) (3R, 4S, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(3-[1,2,4]triazol-1-yl- propoxy )piperidine-1-carboxylic acid Benzyl ester

Add 0.305 g of 1,2,4-triazole sodium salt [41253-21-8] to 0.510 g of (3R, 4S, 5S)-4 in 6 ml of N, N-dimethylformamide at 0°C -[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Azin-6-ylmethoxy]-5-[3-(toluene-4-sulfonyloxy)propoxy]piperidine-1-carboxylate solution, and the mixture was stirred at room temperature for 3 hours . The reaction mixture was poured into ice-water and extracted with tert-butyl methyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf=0.63 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=4.80 (gradient I).

b) [3R, 4S, 5S]-4-[4-[3-methoxypropoxy]phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-[3-(toluene-4-sulfonyloxy) propoxy ]piperidine-1-carboxylic acid benzyl ester

0.500 g of (3S, 4S, 5R)-3-(3-hydroxypropoxy)-4-[4-(3-methoxypropoxy)phenyl]-5-[ 4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 35a) Reaction. The title compound was obtained as a pale yellow oil. Rf = 0.16 (EtOAc-heptane 1:1). Rt = 5.78 (gradient I).

Example 39

N, N-diethyl-2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-acetyl amine

From 0.44 g of (3S, 4R, 5R)-3-diethylcarbamoylmethoxy-4-[4-(3-methoxypropoxy)phenyl]-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate yields the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-diethylcarbamoylmethoxy-4-[4-(3-methoxypropoxy) phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylic acid benzyl ester

0.53 ml of propanephosphonic anhydride [68957-94-8, T3P] (50% in ethyl acetate) was added to 0.517 g of (3S, 4R, 5R)-3-carboxymethoxy in 8 ml of dichloromethane at 0°C Base-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1 , 4] in a solution of oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester, 0.066 g of diethylamine and 0.52 ml of triethylamine, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, and 0.1M aqueous HCl was added. The phases were separated and the aqueous phase was extracted two more times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.2 (EtOAc-heptane 5:1); Rt = 5.20 (gradient I).

b) (3S, 4R, 5R)-3-carboxymethoxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3- methoxy-propyl )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

8ml of 1.5M lithium hydroxide aqueous solution was added to 1.6g of (3S, 4R, 5R)-3-methoxycarbonylmethoxy-4-[4-(3-methoxypropoxy) in 6ml tetrahydrofuran )phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1 -benzyl formate in a solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 2 with 2M HCl. The resulting mixture was extracted twice with 150 ml each of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound was obtained as a colorless oil and used in the next step without further purification. Rt = 4.78 (gradient I).

c) (3S, 4R, 5R)-3-methoxycarbonylmethoxy-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-(3-methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

Add 0.29 g of sodium hydride (60% dispersion in oil) to 3.5 g of (3S,4S,5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]- Benzyl 5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 20b) in solution and the mixture was stirred at room temperature for 1 hour. It was then cooled to -5°C, and 1.30 g of methyl bromoacetate was added dropwise over 1 hour. The reaction mixture was stirred at -5°C for 3 hours and then allowed to warm to room temperature. It was then diluted with tert-butyl methyl ether and poured into 0.5M HCl. The resulting mixture was extracted 3 times with tert-butyl methyl ether. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.22 (EtOAc-heptane 2:1); Rt = 5.26 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 39:

Example

40 N-ethyl-2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-N- methylacetamide

41 2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-N-methyl-N- propylacetamide

46 2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-N- propylacetamide

47 2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-pyrrolidin-1- ylethanone

110 N-ethyl-2-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-N- methylacetamide

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

111 N, N-diethyl-2-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy) -phenyl ]-5-[4-(3-methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}acetamide

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

112 2-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3- methoxypropyl )-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-pyrrolidin-1- ylethanone

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

Example 42

6-[(3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-5-(3-methyl-3H-imidazol-4-yl Methoxy)-piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Zinc

From 0.199 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3-methoxypropyl) in analogy to method B )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(3-methyl-3H-imidazol-4-ylmethoxy)piperidine -1-Benzyl carboxylate afforded the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(3-methyl-3H-triazol-4-ylmethoxy )piperidine-1-carboxylic acid benzyl ester

0.123 g of sodium hydride (60% dispersion in oil) was added to 0.778 g of (3S, 4S, 5R)-hydroxy-4-[4- (3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6- In a solution of benzylmethoxy]piperidine-1-carboxylate (Example 20b) and 0.269 g of 5-chloromethyl-1-methyl-1H-imidazole hydrochloride [90773-41-4] . 0.046 g of tetrabutylammonium iodide was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.20 (dichloromethane-methanol 95:5); Rt = 4.51 (gradient I).

Example 43

6-[(3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-5-(2-[1,2,4]triazol-a-yl-ethyl Oxy)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 1.210 g of (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(2-triisopropylsilyloxyethoxy) Benzyl piperidine-1-carboxylate affords the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-(2-hydroxyethoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From (3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(2-triisopropylsilyloxyethoxy)piperidine-1-carboxylate The title compound was obtained in the form of a pale yellow resin. Rf = 0.14 (EtOAc-heptane 3:1); Rt = 4.87 (gradient 1).

b) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(2- triisopropylsilyloxyethoxy )piperidine-1-carboxylate

0.164 g of sodium hydride (60% dispersion in oil) was added to 2.000 g of (3S,4S,5R)-3-hydroxy-4-[4- (3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6- methoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) solution. The reaction mixture was stirred at room temperature for 10 minutes, and 2.276 g of (2-iodoethoxy)triisopropylsilane [93550-77-7] was added. The reaction mixture was stirred at room temperature for 18 hours, poured into saturated aqueous sodium bicarbonate and extracted with tert-butyl methyl ether. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as an orange oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.61 (EtOAc-heptane 2:1).

Example 45

4-(2-{(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}ethyl)tetrahydropyran-4-ol

Add 0.0594 g of lithium aluminum hydride to 0.288 g of 6-[(3R, 4R, 5S)-5-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)- 4-(4-methoxyphenyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4 ] In the oxazine solution. After 45 minutes at room temperature, the reaction mixture was diluted with 100 ml of tert-butyl methyl ether and carefully quenched with 30 ml of 0.5N NaOH. The aqueous phase was extracted again with 100 ml tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) 6-[(3R,4R,5S)-5-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)-4-(4-methoxyphenyl )piperidine -3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

0.387 g of (3S, 4R, 5R)-3-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)-4-(4-methoxybenzene Base)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid Benzyl ester reaction. The title compound was obtained as a brown oil. Rt = 3.48 (gradient I).

b) (3S, 4R, 5R)-3-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)-4-(4- methoxyphenyl )-5-[4 -(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

0.548 g of (3S, 4R, 5R)-3-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)-4-(4-methoxybenzene) was prepared analogously to Method K Base)-5-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piper Benzyl pyridine-1-carboxylate reaction. The title compound was obtained as a pale yellow oil. Rf = 0.33 (EtOAc-heptane 2:1); Rt = 5.11 (gradient 1).

c) (3S, 4R, 5R)-3-(1,6-dioxaspiro[2.5]oct-2-ylmethoxy)-4-(4- methoxyphenyl )-5-[4 -(3-Methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylic acid benzyl ester

0.236 g of 3-chloroperoxybenzoic acid (70% mCPBA) was added to 0.61 g of (3R,4S,5S)-4-(4-methoxyphenyl)-3- [4-(3-Methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-[2- (tetrahydropyran-4-ylidene)ethoxy]piperidine-1-carboxylic acid benzyl ester solution. After 90 minutes at room temperature, the reaction mixture was diluted with 200 ml tert-butyl methyl ether. The mixture was successively washed with 15 ml of a saturated aqueous solution of sodium carbonate, 15 ml of a saturated aqueous solution of sodium bicarbonate, 30 ml of water and 20 ml of brine. The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.18 (EtOAc-heptane 2:1); Rt = 4.78 (gradient I).

d) (3R, 4S, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro- 2H -Benzo[1,4]oxazin-6-ylmethoxy]-5-[2-(tetrahydropyran-4-ylidene)ethoxy]piperidine -1-carboxylic acid benzyl ester

0.057 g of sodium hydride (60% dispersion in oil) was added to 0.56 g of (3S,4S,5R)-3-hydroxy-4-(4-methoxyphenyl)-5-[ 4-(3-Methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzene methyl ester and 0.546 g of 4-(2-bromoethylene) tetrahydropyran [21378-20-1] in a stirred solution. After 2.5 hours at room temperature, the reaction mixture was diluted with 200 ml tert-butyl methyl ether and washed successively with 15 ml saturated aqueous sodium bicarbonate, 10 ml water and 10 ml brine. The organic phase was dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.20 (EtOAc-heptane 2:1); Rt = 5.10 (gradient I).

e) (3S, 4S, 5R)-3-hydroxyl-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3-oxo- 3,4- Benzyl Dihydro-2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

1.0 g of (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester reaction. The title compound was obtained as a colorless resin. Rf = 0.29 (EtOAc-heptane 2:1); Rt = 4.36 (gradient 1).

f) (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro- 2H -Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1- carboxylate

26.59 g of (3R,4R,5S)-3-hydroxy-4-(4-methoxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl The ester (Example 19d) was reacted with 17.09 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one. The title compound was obtained as a pale yellow resin. Rf = 0.18 (EtOAc-heptane 1:2); Rt = 6.67 (gradient 1).

Example 48

(2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-ethyl)-2-di Methylamine

分子筛加入到1.5ml四氢呋喃中的0.129g的(3R，4R，5S)-4-[4-(3-甲氧基丙氧基)苯基]-3-[4-(3-甲氧基丙基)-3，4-二氢-2H-苯并[1，4]噁嗪-6-基甲氧基]-5-(2-氧代乙氧基)哌啶-1-甲酸苯甲酯溶液中。滴加1ml四氢呋喃中的0.030g二甲胺溶液，并在20℃搅拌反应混合物1小时。经由Hyflo滤掉固体并用四氢呋喃洗涤滤饼。用氩气脱气滤液15分钟，添加0.025g的10％Pd/C之后，在20℃大气压下氢化5小时。滤掉催化剂并使滤液与另外的0.025g的Pd/C和0.155ml的2M HCl混合，并在20℃大气压下氢化12小时。经由Hyflo滤掉催化剂并蒸发滤液。通过闪蒸层析法(SiO₂ 60F)由残余物得到棕色树脂形式的标题化合物。0.100g of 4

Molecular sieves were added to 0.129 g of (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropane) in 1.5ml tetrahydrofuran Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(2-oxoethoxy)piperidine-1-carboxylic acid benzyl ester in solution. A solution of 0.030 g of dimethylamine in 1 ml of tetrahydrofuran was added dropwise and the reaction mixture was stirred at 20° C. for 1 hour. The solid was filtered off through Hyflo and the filter cake was washed with THF. The filtrate was degassed with argon for 15 minutes, and after addition of 0.025 g of 10% Pd/C, hydrogenated at 20° C. for 5 hours under atmospheric pressure. The catalyst was filtered off and the filtrate was mixed with a further 0.025 g of Pd/C and 0.155 ml of 2M HCl and hydrogenated at 20°C for 12 hours at atmospheric pressure. The catalyst was filtered off through Hyflo and the filtrate was evaporated. The title compound is obtained from the residue as a brown resin by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(2-oxoethoxy)piperidine-1- carboxylic acid benzyl ester

From 1.121 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(2-triisopropylsilyloxyethoxy The title compound was prepared from benzyl piperidine-1-carboxylate (Example 43a). The title compound is obtained from the residue as a brown resin by flash chromatography ( _SiO2 60F). Rf = 0.18 (EtOAc-heptane 3:1); Rt = 4.74 (gradient I).

Example 49

6-{(3R, 4S, 5S)-4-(4-methoxyphenyl)-5-[2-(4-methoxytetrahydropyran-4-yl)ethoxy Base]piperidin-3-yloxymethyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.169 g of (3R,4S,5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-[2-(4-methoxytetrahydropyran-4-yl)ethoxy]piperidine-1- Benzyl formate to prepare the title compound.

The starting materials were prepared as follows:

a) (3R, 4S, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1 ,4]oxazin-6-ylmethoxy]-5-[2-(4-methoxytetrahydropyran-4-yl)ethoxy]piperidine -1-carboxylic acid benzyl ester

Add 0.014 g of sodium hydride (60% dispersion in oil) to 0.166 g of (3S,4S,5R)-3-[2 -(4-Hydroxytetrahydropyran-4-yl)ethoxy]-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester and 0.074ml methyl iodide solution. After 3 hours at room temperature, a further 0.014 g of sodium hydride (60% dispersion in oil) and 0.074 ml of methyl iodide were added. After 14 hours at room temperature, the reaction mixture was diluted with tert-butyl methyl ether and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated. The crude title compound was obtained from the residue as an opaque oil. Rf = 0.75 (EtOAc); Rt = 5.31 (gradient I).

b) (3S, 4S, 5R)-3-[2-(4-hydroxytetrahydropyran-4-yl)ethoxy]-4-(4- methoxyphenyl )-5-[4- Benzyl (3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylate

0.135 g of 4-(2-{(3S,4S,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl) -3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}ethyl)tetrahydropyran-4-ol (implementation Example 45) reaction. The title compound was obtained as a brown oil. Rf = 0.43 (EtOAc); Rt = 4.87 (gradient I).

Example 50

6-[(3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-5-(2-morpholin-4-ylethoxy)- Piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.191 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3-methoxypropyl) in analogy to method B )-3,4-dihydro-2H-benzo[1,4]oxazin-4-ylmethoxy]-5-(2-morpholin-4-yl-ethoxy)piperidine-1- Benzyl formate afforded the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(2-morpholin-4-ylethoxy)piperidine -1-carboxylic acid benzyl ester

0.279 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)-phenyl]-3-[4-(3-methoxypropyl) was prepared analogously to Method K )-3,4-dihydro-2H-benzo[1,4]oxazin-4-ylmethoxy]-5-(2-morpholin-4-yl-2-oxoethoxy)piper Benzyl pyridine-1-carboxylate reaction. Methanolysis was carried out with 7 ml of methanol at 65°C for 24 hours. The title compound was obtained as a colorless oil. Rt = 4.46 (gradient I).

b) (3R, 4R, 5S)-4-[4-(3-methoxypropoxy)phenyl]-3-(4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-(2-morpholin-4-yl-2- oxoethoxy )piperidine-1-carboxylic acid benzyl ester

0.276 g of (3S, 4R, 5R)-3-carboxymethoxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 39b) and 0.045ml morpholine reaction. The title compound was obtained as a pale yellow oil. Rt = 4.87 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 50:

Example 54

6-[(3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-5-(2-pyrrolidin-1-ylethoxy) Piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

Example 51

(3S, 4S, 5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ol

From 0.360 g of (3S, 4S, 5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) to afford the title compound.

Example 52

6-{(3R, 4S, 5S)-4-[4-(3-methoxypropoxy)phenyl]-5-propoxypiperidin-3-yloxy Methyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.255 g of (3S, 4S, 5R)-3-allyloxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3 -Benzyl-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate affords the title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-allyloxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3- methoxypropyl ) Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

From 0.400 g of (3S, 4S, 5R)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 20b) and 0.11 ml allyl bromide to give the title compound as a yellow resin. Rf = 0.13 (EtOAc-heptane 1:1); Rt = 5.64 (gradient 1).

Example 53

2-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-N,N-dimethyl Acetamide

From 0.262 g of (3S, 4R, 5R)-3-dimethylcarbamoylmethoxy-4-[4-(3-methoxypropoxy)phenyl]-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate yields the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-dimethylcarbamoylmethoxy-4-[4-(3-methoxypropoxy) phenyl]-5-[4-(3-methyl Oxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylic acid benzyl ester

0.266 g of (3S,4R,5R)-3-methoxycarbonylmethoxy-4-[4-(3-methoxypropoxy) in 14 ml of dimethylamine (33% in ethanol) was stirred at 60 °C Base) phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine - Benzyl 1-carboxylate (Example 39c) solution for 24 hours. The reaction mixture was evaporated. The crude title compound is obtained from the residue as a yellow oil. Rt = 4.88 (gradient I).

Example 55

2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-((S)-3-methylmorpholin-4-yl)ethanone

From 0.065 g of 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-yloxy]-1-((S )-3-methylmorpholin-4-yl)ethanone to prepare the title compound.

The starting materials were prepared as follows:

a) 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3- yloxy ]-1-((S)-3-methylmorpholine -4-yl)ethanone

0.389 ml of propanephosphonic anhydride [68957-94-8, T3P] (50% in ethyl acetate) was added to 0.40 g of (3S, 4R, 5R)-4-[4- (3-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy ]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetic acid, 0.0671 g of (S)-3-methylmorpholine [350595-57-2] and 0.385 ml of triethylamine solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, and 0.2M HCl was added. The phases were separated and the aqueous phase was extracted two more times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.53 (EtOAc); Rt = 4.93 (gradient I).

b) [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetic acid

5ml of 1.5M lithium hydroxide aqueous solution was added to 0.75g of [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy] methyl acetate (Example 28b) solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 2 with 1M HCl. The resulting mixture was extracted twice with 80 ml each of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound was obtained as a yellow oil and used in the next step without further purification. Rf = 0.15 (EtOAc); Rt = 4.70 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 55:

Example

56 2-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-2-yloxy}-1-((S)-2-methylpiperidin-1-yl) ethanone

57 1-((3S, 5S)-3,5-dimethylmorpholin-4-yl)-2-{(3S, 4R, 5R)-4-(4- methoxyphenyl ) -5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3- yloxy}ethanone

58 2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-((R)-3-methylmorpholin-4-yl) ethanone

61 1-((3S, 5R)-3,5-dimethylmorpholin-4-yl)-2-{(3S, 4R, 5R)-4-(4- methoxyphenyl ) -5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3- yloxy}ethanone

75 1-((2S, 6R)-2,6-dimethylpiperidin-1-yl)-2-{(3S, 4R, 5R)-4-(4- methoxyphenyl )-5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3- yloxy}ethanone

79 2-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-((R)-2-methylpiperidin-1-yl) ethanone

99 2-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-((R)-2-methylpyrrolidin-1- yl)ethanone

100 N, N-diisopropyl-2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl )-3, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}acetamide

101 2-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-piperidin-1-yl-ethanone

Example 59

6-{(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-[2-(S)-3-methylmorpholin-4-yl)ethoxy] Piperidin-3-yloxymethyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

From 0.439 g of 6-[(3R,4R,5S)-4-(4-methoxyphenyl)-5-[2-((S)-3-methylmorpholine-4 -yl)ethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro- 2H-Benzo[1,4]oxazine The title compound was prepared.

The starting materials were prepared as follows:

a) 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-[2-((S)-3-methylmorpholin-4-yl) ethoxy ] -1-(Toluene-4-sulfonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1,4 ] Oxazine

2ml of borane-THF complex solution (1M in THF) was added to 0.493g of 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) piperidin-3-yloxy]-1-((S)-3-methylmorpholin-4-yl)ethanone solution, and the mixture was stirred at 55°C for 16 hours. The reaction mixture was then mixed with 10 ml methanol and heated at 65°C for 2 hours. The solution was evaporated in vacuo and the title compound was obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.07 (EtOAc); Rt = 4.52 (gradient I).

b) 2-[(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3- yloxy ]-1-((S)-3-methylmorpholine -4-yl)ethanone

0.389 ml of propanephosphonic anhydride [68957-94-8, T3P] (50% in ethyl acetate) was added to 0.40 g of (3S, 4R, 5R)-4-(4- Methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)piperidin-3-yloxy]acetic acid, 0.0671g of (3S)-3-methylmorpholine [350595-57-2] and 0.385ml of triethylamine solution, And the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, and 0.2M HCl was added. The phases were separated and the aqueous phase was extracted two more times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.53 (EtOAc); Rt = 4.93 (gradient I).

c) [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy]acetic acid

5ml of 1.5M lithium hydroxide aqueous solution was added to 0.75g of [(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yloxy] methyl acetate (Example 28b) solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 2 with 1M HCl. The resulting mixture was extracted twice with 80 ml each of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound was obtained as a yellow oil and used in the next step without further purification. Rf = 0.15 (EtOAc); Rt = 4.70 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 59:

Example

60 6-{(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-[2-(R)-3-methylmorpholin-4-yl) ethoxy ]piperidine -3-yloxymethyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

62 6-{(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-[2-((S)-2-methylpiperidin-1-yl) ethoxy ]piper Pyridin-3-yloxymethyl}-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

63 6-[(3R, 4R, 5S)-5-[2-((3S, 5S)-3,5-dimethylmorpholin-4-yl)ethoxy]-4-(4- methoxy phenyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

68 6-[(3R, 4R, 5S)-5-[2-((3R, 5S)-3,5-dimethylmorpholin-4-yl)ethoxy]-4-(4- methoxy phenyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

76 6-[(3R,4R,5S)-5-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethoxy]-4-(4- methoxy phenyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine

Example 64

((R)-2-{(3S,4R,5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-methylethyl) Dimethylamine

From 0.118 g of (3S, 4R, 5R)-3-((R)-2-dimethylaminopropoxy)-4-[4-(3-methoxypropoxy) in analogy to method B Phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- Benzyl formate to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2-dimethylaminopropoxy)-4-[4-(3-methoxypropoxy) phenyl]-5-[ Benzyl 4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

0.177 g of (3S,4R,5R)-3-((S)-2-methanesulfonyloxypropoxy)-4-[4 in 5 ml of dimethylamine (33% in ethanol) was stirred at 50°C -(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6 -Ylmethoxy]piperidine-1-carboxylic acid benzyl ester solution for 20 hours and then evaporated. The residue was diluted with 100 ml of tert-butyl methyl ether, and washed with 20 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with 100 ml tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The crude title compound is obtained from the residue as a yellow oil. Rt = 4.70 (gradient I).

b) (3S, 4R, 5R)-3-((S)-2-methanesulfonyloxypropoxy)-4-[4-(3- methoxypropoxy )phenyl]-5- Benzyl [4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine -1-carboxylate

0.034ml of methanesulfonyl chloride was added to 0.27g of (3S, 4R, 5R)-3-((S)-2-hydroxypropoxy)-4-[4-(3 -methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl Oxy]piperidine-1-carboxylic acid benzyl ester and 0.066ml triethylamine solution. After 1 hour at 0°C, an additional 0.005 ml of methanesulfonyl chloride and 0.012 ml of triethylamine were added to the reaction solution. After 6 hours at room temperature, the reaction mixture was diluted with 200 ml of tert-butyl methyl ether and washed successively with 20 ml of 0.1N HCl, 30 ml of saturated aqueous sodium bicarbonate, 20 ml of water and 10 ml of brine. The organic phase was dried over sodium sulfate and evaporated. The crude title compound is obtained from the residue as a yellow oil. Rf = 0.30 (EtOAc-heptane 2:1); Rt = 5.27 (gradient 1).

c) (3S, 4R, 5R)-3-((S)-2-hydroxypropoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

0.347 g of (S)-1-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-prop-2- Alcohol (Example 44) was reacted. The title compound was obtained as a colorless resin. Rf = 0.21 (EtOAc-heptane 2:1); Rt = 5.03 (gradient 1).

The following compounds were prepared in a manner analogous to the method described in Example 64:

Example 65

((S)-2-{(3S,4R,5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}-1-methylethyl) Dimethylamine

Example 66

(R)-1-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-butan-2-ol

From 0.280 g of (3R,4R,5S)-3-((R)-2-hydroxybutoxy)-4-[4-(3-methoxypropoxy)phenyl] analogously to method B -3-[4-(3-methoxypropoxy)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzene The methyl ester afforded the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-3-((R)-2-hydroxybutoxy)-4-[4-(3-methoxybutoxy) phenyl ]-3-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

Dissolve 0.010 g of copper(I) cyanide in 5 ml of dry tetrahydrofuran under argon in a heat-dried Schlenk tube. The suspension was cooled to -78°C and 0.30 ml of methylmagnesium bromide solution (35% in diethyl ether) was added dropwise. Add 0.475 g of (3R,4R,5S)-4-[4-(3-methoxypropoxy)phenyl]-3-[4-(3-methoxypropyl) in 4 ml dry tetrahydrofuran -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-oxiranylmethoxy)piperidine-1-carboxylic acid Benzyl ester (Example 36a) and the reaction mixture was stirred at -78°C for 30 minutes and then allowed to warm to 20°C over 16 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and adjusted to pH 10 with 25% aqueous ammonium hydroxide. The mixture was extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.15 (EtOAc-heptane 2:1); Rt = 5.22 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 66:

Example

67 (R)-1-{(3S, 4R, 5R)-4-[4-(3-methoxypropoxy)-phenyl]-5-[4-(3-methoxypropyl ) -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-butan-2-ol using toluene-4-sulfonic acid (S)-1-Oxiranyl methyl ester[70987-78-9]

106 (S)-1-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-butan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methyl Oxybutoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy ]-piperidine-1-carboxylic acid benzyl ester (example 78a) starting.

108 (R)-1-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}butan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

113 (S)-1-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}pentan-2-ol

Using ethylmagnesium bromide solution (1M in tetrahydrofuran), using toluene-4-sulfonic acid (S)-1-oxiranylmethyl ester [70987-78-9], from (3S, 4S, 5R)- 3-Hydroxy-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[ 1,4]Oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester (Example 78a) starting.

114 (R)-1-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}pentan-2-ol

From (3S,4S,5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4 -(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 78a) Start.

125 (S)-1-{(3S, 4R, 5R)-4-[4-(3-methoxy-propoxy)-phenyl]-5-[4-(3-methoxy- propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-pentan-2- ol

From (3S, 4S, 5R)-3 -Hydroxy-4-[4-(3-methoxy-propoxy)-phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]Oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 20b) started.

126 (R)-1-{(3S, 4R, 5R)-4-[4-(3-methoxy-propoxy)-phenyl]-5-[4-(3-methoxy- propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-pentan-2- ol

From (3S,4S,5R)-3-hydroxy-4-[4-(3-methoxy-propoxy)-phenyl]-5-[ 4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (implementation Example 20b) begins.

Example 69

(R)-1-methoxy-3-[(3S,4R,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]-4-(4-methylthiophenyl)piperidin-3-yloxy]propan-2-ol

Add 3 ml of 40% aqueous potassium hydroxide to 0.047 g of (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy in 3 ml of methanol and 1 ml of dioxane )-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(4-methyl thiophenyl)piperidine-1-carboxylic acid benzyl ester solution. The reaction mixture was heated at reflux for 3 hours. It was then diluted with 40 ml of water and extracted three times with 40 ml each of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-5-[4-(3- methoxypropyl )-3,4- Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(4-methylthiophenyl)piperidine-1- carboxylate

0.068 g of (3S,4S,5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1, 4] oxazin-6-ylmethoxy]-4-(4-methylthiophenyl)piperidine-1-carboxylate benzyl ester and 0.023 g of S-(+)-glycidyl methyl ether [64491-68-5] Response. The title compound is obtained as a yellow oil. Rf = 0.20 (EtOAc-heptane 2:1); Rt = 5.04 (gradient 1).

b) (3S, 4S, 5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine-6- Benzylmethoxy]-4-(4-methylthiophenyl)}piperidine-1-carboxylate

0.095 g of (3R,4R,5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine was prepared analogously to Method J -6-ylmethoxy]-4-(4-methylthiophenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester reaction. The title compound is obtained as a yellow oil. Rf = 0.13 (EtOAc-heptane 1:1); Rt = 4.95 (gradient 1).

c) (3R, 4R, 5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy ]-4-(4-Methylthiophenyl)-5-triisopropylsilyloxypiperidine-1-carboxylate benzyl ester

0.477 g of cesium fluoride was added to 0.718 g of (3R,4R,5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H in 15 ml of DMF under argon -Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxy-4-(4-triisopropylsilylthiophenyl)piperidine-1-carboxylic acid Benzyl ester in a degassed solution, and the mixture was stirred at room temperature for 2 hours. The mixture was then cooled to -12°C and, after addition of 0.060 ml methyl iodide, stirred at this temperature for 3 hours. The reaction mixture was diluted with tert-butyl methyl ether and poured into water. The organic phase was dried over sodium sulfate, filtered and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.56 (EtOAc-heptane 1:1).

d) (3R, 4R, 5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy ]-5-triisopropylsilyloxy-4-(4-triisopropylsilylthiophenyl)piperidine-1- carboxylic acid benzyl ester

0.323 g of sodium tert-butoxide was added to 0.73 ml of triisopropylsilanethiol in 7 ml of toluene in a Schlenk tube at 0 °C, and the mixture was stirred at room temperature for 45 minutes. In a second flask, 2.0 g of (3R,4R,5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[ 1,4] oxazin-6-ylmethoxy]-4-(4-trifluoromethanesulfonyloxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester ( Example 72c) was dissolved in 7 ml of toluene and 0.415 g of tetrakistriphenylphosphinepalladium(0) was added. This suspension was added to the above "thiolate" solution which had been preheated to 90°C and stirred overnight at 90°C under argon. The reaction mixture was diluted with tert-butyl methyl ether and poured into water. The organic phase was dried over sodium sulfate, filtered and evaporated. The title compound is obtained as a brown oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.39 (EtOAc-heptane 1:2).

The following compounds were prepared in a manner analogous to the method described in Example 69:

Example

70 (R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(2-methoxyethylthio) phenyl ]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3- yloxy}propan-2-ol

71 (R)-1-methoxy-3-{(3S, 4R, 5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-4-[4-(3-methoxypropylthio)phenyl]piperidin-3-yloxy}propan- 2-ol

103 (R)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy) -phenyl ]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}propan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

104 (S)-1-methoxy-3-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy) -phenyl ]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3- yloxy}propan-2-ol

Using R-(-)-glycidyl methyl ether [64491-70-9], from (3S,4S,5R)-3-hydroxy-4-[4-(4-methoxybutoxy)benzene Base]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1- Benzyl formate (Example 78a) started.

Example 72

4-{(3S,4S,5R)-3-Hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxa Azin-6-ylmethoxy]piperidin-4-yl}benzonitrile

From 0.0538 g of (3S,4S,5R)-4-(cyanophenyl)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-di Benzyl hydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate affords the title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-4-(4-cyanophenyl)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4- dihydro -2H- benzene And[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester

1.290 g of (3S,4S,5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4 in 11 ml of dry N,N-dimethylformamide at 120°C -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(trifluoromethanesulfonyloxyphenyl)piperidine-1-carboxylic acid benzyl ester, 0.440g cyanide Zinc(II) and 0.193 g tetrakistriphenylphosphine palladium(0) were heated for 16 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with tert-butyl methyl ether. The combined organic phases were washed with brine, dried and evaporated. The title compound is obtained as a colorless resin from the residue by flash chromatography ( _SiO2 60F). Rf = 0.11 (EtOAc-heptane 3:2); Rt = 4.61 (gradient I).

b) (3S, 4S, 5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine-6- Benzylmethoxy]-4-(trifluoromethanesulfonyloxyphenyl)}piperidine-1-carboxylate

From 2.340 g of (3S,4R,5R)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine in analogy to Method J Benzyl-6-ylmethoxy]-4-(trifluoromethanesulfonyloxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylate affords the title compound as a pale yellow resin. Rf = 0.37 (EtOAc-heptane 2:1); Rt = 5.20 (gradient 1).

c) (3S, 4R, 5R)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy ]-4-(4-Trifluoromethanesulfonyloxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester

0.544ml of triethylamine was added to 2.590g of (3R,4R,5S)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl) in 20ml of dry dichloromethane Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylate (Example 11d ) and 1.353g of N-phenyl-bis(trifluoromethanesulfonamide) solution. The reaction solution was left standing at room temperature for 3 hours and then evaporated to dryness. The title compound is obtained as a reddish oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.56 (EtOAc-heptane 1:1).

Example 73

4-{(3S, 4R, 5R)-3-((R)-2-hydroxy-3-methoxypropoxy)-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-4-yl}benzonitrile

From 0.065 g of (3S,4S,5R)-4-(4-cyanophenyl)-3-((R)-2-hydroxy-3-methoxypropoxy)-5 in analogy to method B -[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester to give title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-4-(4-cyanophenyl)-3-((R)-2-hydroxy-3- methoxypropoxy )-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 0.100 g of (3S,4S,5R)-4-(4-cyanophenyl)-3-hydroxyl-5-[4-(3-methoxypropyl)-3,4 in analogy to method M -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 72a) and 0.061 of S-(+)-glycidyl Methyl ether [64491-68-5] gave the title compound as a colorless resin. Rf = 0.16 (EtOAc-heptane 2:1); Rt = 4.68 (gradient 1).

The following compounds were prepared in a manner analogous to the method described in Example 73:

Example 74

4-{(3S, 4R, 5R)-3-((S)-2-hydroxy-3-methoxypropoxy)-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-4-yl}benzonitrile

Example 77

7-{(3R,4S,5S)-5-Hydroxy-4-[4-(3-methoxypropoxy)phenyl]piperidin-3-yloxymethyl base}-3,3-dimethyl-1,3-dihydroindolin-2-one

From 0.350 g of (3R,4S,5S)-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-7-ylmethoxy The title compound was prepared from benzyl)-5-hydroxy-4-[4-(3-methoxypropoxy)phenyl]piperidine-1-carboxylate.

The starting materials were prepared as follows:

a) (3R, 4S, 5S)-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-7-ylmethoxy )-5-hydroxyl- Benzyl 4-[4-(3-methoxypropoxy)phenyl]piperidine-1-carboxylate

Add 40ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) to 1.78g of (3R, 4R, 5S)-3-[3,3-dimethyl-2-oxo-1- (2-Trimethylsilylethoxymethyl)-2,3-dihydro-1H-indol-7-ylmethoxy]-4-[4-(3-methoxypropoxy) phenyl]-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester solution, and the mixture was stirred at reflux temperature for 4 days. The reaction mixture was poured into ice-water and extracted with tert-butyl methyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated. The title compound is obtained as a white foam from the residue by flash chromatography ( _SiO2 60F). Rf = 0.20 (EtOAc-heptane 1:1); Rt = 4.54 (gradient I).

b) (3R, 4R, 5S)-3-[3,3-dimethyl-2-oxo-1-(2- trimethylsilylethoxymethyl )-2,3-dihydro- Benzyl 1H-indol-7-ylmethoxy]-4-[4-(3-methoxypropoxy)phenyl]-5-triisopropylsilyloxypiperidine -1-carboxylate

2.0 g of (3R, 4R, 5S)-3-hydroxy-4-[4-(3-methoxypropoxy)phenyl]-5-triisopropylsilyloxypipe Benzyl pyridine-1-carboxylate (Example 20e) and 1.60 g of 7-bromomethyl-3,3-dimethyl-1-(2-trimethylsilylethoxymethyl)-1, 3-Indolin-2-one [985278-97-8] reaction. The title compound was obtained as a colorless oil. Rf = 0.22 (EtOAc-heptane 1:4).

Example 78

(3S, 4S, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ol

From 0.264 g of (3S,4S,5R)-3-hydroxy-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxy The title compound was prepared from benzyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl )-3 , 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester

1.11 g of (3R, 4R, 5S)-4-[4-(4-methoxybutoxy)phenyl]-3-[4-(3-methoxypropyl) similarly to Example 1b )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester reaction. The title compound was obtained as an opaque white oil. Rf = 0.60 (EtOAc); Rt = 4.94 (gradient I).

b) (3R, 4R, 5S)-4-[4-(4-methoxybutoxy)-phenyl]-3-[4-(3- methoxypropyl )-3,4-bis Benzyl Hydrogen-2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1- carboxylate

From 1.15 g of (3R,4R,5S)-3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine- Benzyl 1-carboxylate (example 11h) and 0.461 g of 1-bromo-3-methoxypropane [4457-67-4] prepared the title compound. Rf = 0.19 (EtOAc-heptane 1:1).

Example 80

(3S, 4S, 5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl Oxy]-4-[4-(3-Methylthiopropoxy)phenyl]piperidin-3-ol

Add 5 ml of 40% potassium hydroxide aqueous solution to 0.38 g of (3S, 4S, 5R)-3-hydroxyl-5-[4-(3-methoxypropyl) in 5 ml of methanol and 2 ml of dioxane -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(3-methylthiopropoxy)phenyl]piperidine- 1-Benzyl formate solution. The reaction mixture was heated at reflux for 3 hours. It was then diluted with 40 ml of water and extracted three times with 40 ml each of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine-6- Benzylmethoxy]-4-[4-(3-methylthiopropoxy)phenyl]piperidine-1-carboxylate

1.2 g of (3R,4R,5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine were prepared analogously to Method J -6-ylmethoxy]-4-[4-(3-methylthiopropoxy)phenyl]-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester. The title compound was obtained as a colorless resin. Rf = 0.18 (EtOAc-heptane 4:1); Rt = 5.15 (gradient 1).

b) (3R,4R,5S)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy ]-4-[4-(3-Methylthiopropoxy)phenyl]-5-triisopropylsilyloxypiperidine-1- carboxylic acid benzyl ester

3.0 g of (3R,4R,5S)-4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H -Benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1-benzoic acid benzyl ester (Example 11d) and 1.49 g of 3-methyl Thiopropyltoluene-4-sulfonate [187722-18-5] reaction. The title compound is obtained as a yellow oil. Rf = 0.18 (EtOAc-heptane 1:2).

Example 81

(3S, 4S, 5R)-4-[4-(4-methoxybutylthio)phenyl]-5-[4-(3-methoxypropyl)-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ol

0.33 g of (3R, 4R, 5S)-4-[4-(4-methoxybutylthio)benzene in 5ml of dioxane, 6ml of 40% aqueous potassium hydroxide solution and 6ml of methanol at 90°C Base]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropyl The solution of benzylsiloxypiperidine-1-carboxylate was stirred for 4 days. The reaction mixture was diluted with 50 ml tert-butyl methyl ether and mixed with 20 ml water at room temperature. The aqueous phase was then extracted with 2 x 50 ml tert-butyl methyl ether. The combined organic phases were washed with 20 ml of brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(4-methoxybutylthio)-phenyl]-3-[4-(3- methoxypropyl )-3,4- Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1- carboxylate

From (3R,4R,5S)-4-[4-(4-methoxybutylthio)phenyl]-3-[4-(3-methoxy Propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine-1 -Benzyl formate gives the title compound as a colorless oil. Rf = 0.40 (EtOAc-heptane 1:1).

b) (3R, 4R, 5S)-4-[4-(4-methoxybutylthio)phenyl]-3-[4-(3- methoxypropyl )-3-oxo- Benzyl 3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine- 1-carboxylate

From (3R, 4R, 5S)-3-hydroxyl-4-[4-(4-methoxybutylthio)phenyl]-5-triisopropylsilyloxypiperidine in analogy to Example 16b -Benzyl 1-carboxylate afforded the title compound as a yellow oil. Rf = 0.45 (EtOAc-heptane 1:1); Rt = 7.38 (gradient 1).

c) (3R, 4R, 5S)-3-hydroxy-4-[4-(4-methoxybutylthio)phenyl]-5-triisopropylsilyloxypiperidine- 1-carboxylic acid benzene methyl ester

From (3R,4R,5S)-3-hydroxy-5-triisopropylsilyloxy-4-(4-triisopropylsilylthiophenyl)piperidine-1- in analogy to Example 69c Benzyl formate and 1-bromo-3-methoxypropane [4457-67-4] gave the title compound as a yellow oil. Rf = 0.40 (EtOAc-heptane 1:1); Rt = 6.76 (gradient I).

d) Benzyl (3R, 4R, 5S)-3-hydroxy-5-triisopropylsilyloxy-4-(4-triisopropylsilylthiophenyl )piperidine-1-carboxylate

From (3R,4R,5S)-3-hydroxy-4-(4-trifluoromethanesulfonyloxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid in analogy to Example 69d Benzyl ester afforded the title compound as a red oil. Rf = 0.07 (EtOAc-heptane 1:4).

e) Benzyl (3R,4R,5S)-3-hydroxy-4-(4-trifluoromethanesulfonyloxyphenyl)-5- triisopropylsilyloxypiperidine - 1-carboxylate

From (3R,4R,5S)-3-hydroxy-4-(4-hydroxyphenyl)-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester in analogy to Example 72c (Example 19d) The title compound is obtained in the form of a pale yellow resin. Rf = 0.58 (EtOAc-heptane 1:1); Rt = 6.61 (gradient 1).

The following compounds were prepared in a manner analogous to the method described in Example 81:

Example 82

(3S, 4S, 5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl Oxy]-4-[4-(3-methoxypropylthio)phenyl]piperidin-3-ol

Example 83

(3S, 4S, 5R)-4-[4-((R)-4-methoxy-3-methylbutylthio)-phenyl]-5-[4-(3-methoxy propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ol

0.44 g of (3S, 4S, 5R)-3-hydroxy-4-[4-((R)-4-methanol) in 1 ml of dioxane, 0.7 ml of 40% aqueous KOH and 1.2 ml of methanol at 90 °C Oxy-3-methylbutylthio)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine- The solution of methyl 6-ylmethoxy]-piperidine-1-carboxylate was stirred for 1 hour. The reaction mixture was diluted with tert-butyl methyl ether and mixed with water at room temperature. The aqueous phase was extracted with tert-butyl methyl ether (2x). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-hydroxyl-4-[4-((R)-4-methoxy-3-methylbutylthio) phenyl ]-5-[4-(3 -Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid methyl ester

0.31 g of (3R, 4R, 5S)-4-[4-((R)-4-methoxy-3-methylbutylthio)phenyl]-3-[ 4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilyloxypiperidine - Reaction of methyl 1-formate. The title compound was obtained as a colorless oil. Rf = 0.15 (EtOAc-heptane 2:1); Rt = 4.73 (gradient 1).

b) (3R, 4R, 5S)-4-[4-((R)-4-methoxy-3-methylbutylthio)phenyl]-3-[4-(3- methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5- triisopropylsilyloxypiperidine - 1-carboxylic acid methyl ester

From 0.5 g of (3R,4R,5S)-3-hydroxy-4-[4-((R)-4-methoxy-3-methylbutanol in a manner similar to that described in Example 81a-b Methylsulfanyl)phenyl]-5-triisopropylsilyloxypiperidine-1-carboxylate affords the title compound as a colorless oil. Rf = 0.53 (EtOAc-heptane 1:1).

c) (3R, 4R, 5S)-3-hydroxy-4-[4-((R)-4-methoxy-3-methylbutylthio) phenyl ]-5-triisopropylsilane Methyl oxypiperidine-1-carboxylate

10.9 g of sodium methoxide was added to 2.09 g of (3R, 4R, 5S)-3-hydroxyl-4-{4-[(R)-3-methyl-4-(toluene-4 -sulfonyloxy)butylthio]phenyl}-5-triisopropylsilyloxypiperidine-1-carboxylic acid benzyl ester solution. The reaction mixture was stirred at 50°C until conversion was complete, then diluted with 150 ml tert-butyl methyl ether at room temperature. The mixture was washed with 40 ml of saturated aqueous sodium carbonate, 100 ml of water and 30 ml of brine. The organic phase was dried over sodium sulfate and evaporated. The crude title compound is obtained from the residue as a pale yellow oil. Rf = 0.50 (EtOAc-heptane 1:1); Rt = 6.53 (gradient 1).

d) (3R, 4R, 5S)-3-hydroxy-4-{4-((R)-3-methyl-4-(toluene-4-sulfonyloxy)butylthio]-phenyl } -Benzyl 5-triisopropylsilyloxypiperidine-1-carboxylate

1.5 g of (3R, 4R, 5S)-3-hydroxyl-5-triisopropylsilyloxy-4-(4-triisopropylsilylthiophenyl)piperidine was prepared in a similar manner to Example 81c - Benzyl 1-carboxylate (example 81d) was reacted with 1.5 g of (R)-2-methylbutan-1,4-diol xylenesulfonate [281214-26-4]. The title compound is obtained as a yellow oil. Rf = 1.6 (EtOAc-heptane 1:2).

Example 87

Isopropyl-{(3S,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amine

From (3R,4R,5R)-3-(isopropylaminomethyl)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl) analogously to Method B )-3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester to start the preparation of the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5R)-3-(isopropylaminomethyl)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

0.50 mmol of (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl) A solution of benzyl piperidine-1-carboxylate and 1.0 mmol of isopropylamine was stirred for 8 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (3x). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf=0.29 (dichloromethane-methanol-25% concentrated ammonia water=200:10:1); Rt=4.45 (gradient I).

b) (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1 ,4] oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)piperidine-1-carboxylate benzyl ester

From (3S,4R,5R)-3-hydroxymethyl-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4 in analogy to method H -Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate initially gave the title compound as a yellow oil. The crude title compound was used in the next step. Rf = 0.39 (EtOAc-heptane = 2:1).

c) (3S, 4R, 5R)-3-hydroxymethyl-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro- 2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester

From (3S, 4R, 5R)-3-hydroxymethyl-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl) in a manner similar to that described in Example 11d Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate initially gave the title compound as a yellow oil. Rf = 0.18 (EtOAc-heptane = 2:1); Rt = 4.79 (gradient I).

d) (3S, 4R, 5R)-3-hydroxymethyl-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3-oxo- 3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

Make 1.87 g of (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo in 20ml methanol and 4ml THF -3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-trityloxymethylpiperidine-1-carboxylic acid benzyl ester solution with 1.53 g of p-toluenesulfonic acid monohydrate were mixed and stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x). The combined organic phases were dried over sodium sulfate and evaporated. The crude title compound was used in the next step.

e) (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro- 2H -Benzo[1,4]oxazin-6-ylmethoxy]-5-trityloxymethylpiperidine-1-carboxylic acid benzyl ester

From (3R,4R,5S)-3-hydroxy-4-(4-methoxyphenyl)-5-trityloxymethylpiperidine-1-carboxylic acid benzyl ester analogously to method D The title compound as a colorless wax. Rf = 0.26 (EtOAc-heptane = 1:1); Rt = 6.25 (gradient I).

f) (3R,4R,5S)-3-Hydroxy-4-(4-methoxyphenyl)-5-trityloxymethylpiperidine- 1-carboxylic acid benzyl ester

From (3R,4R,5S)-1-benzyl-4-(4-methoxyphenyl) in analogy to method B (3:1 methanol-tetrahydrofuran used as solvent) and in Example 11h -5-trityloxymethylpiperidin-3-ol (L)-(+)-mandelate [303043-54-1] initially gave the title compound as a yellow oil. The crude title compound was used in the next step. Rf = 0.25 (EtOAc-heptane = 1:1).

The following compounds were prepared in a manner analogous to the method described in Example 87:

Example

88 tert-butyl-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amine

89 (2-methoxyethyl)-{(3R,4R,5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl )-3,4 -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amine

90 6-[(3R, 4R, 5S)-4-(4-methoxyphenyl)-5-morpholin-4-ylmethylpiperidin-3- yloxymethyl ]-4-(3 -methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine

Example 91

N-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}acetamide

From (3R,4R,5R)-3-(acetylaminomethyl)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl) analogously to method B -Benzyl 3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate Preparation of the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5R)-3-(acetylaminomethyl)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4 -Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate

At 0°C, 3 mmol of triethylamine was added to 1 mmol of (3R, 4R, 5R)-3-aminomethyl-4-(4-methoxyphenyl)-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester and 1.1 mmol of acetyl chloride in solution. After 1.5 hours, the reaction mixture was poured into 1M sodium bicarbonate solution and extracted with tert-butyl methyl ether (3x), the combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf=0.29 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=4.58 (gradient I).

b) (3R, 4R, 5R)-3-aminomethyl-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro- 2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate benzyl ester

Add 0.195 ml of 25% concentrated ammonia solution in 0.9 ml of methanol to 200 mg of (3S,4R,5R)-3-azidomethyl-4-(4-methanol in 0.95 ml of tetrahydrofuran and 0.23 ml of water at room temperature Oxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine- 1-Benzyl formate solution. After addition of 128 mg of triphenylphosphine, the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with half saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf=0.31 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=4.24 (gradient I).

c) (3S, 4R, 5R)-3-azidomethyl-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

0.50mmol of (3R,4R,5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4 in 5ml of DMPU at 80°C -Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)piperidine-1-carboxylic acid benzyl ester (Example A solution of 87b) and 2 mmol of sodium azide was stirred for 4 hours. The reaction mixture was diluted with water and extracted with tert-butyl methyl ether (3x). The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained as a pale yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.33 (EtOAc-heptane = 1:1); Rt = 5.61 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 91:

Example

92 N-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}propionamide

115 Morpholine-4-carboxylic acid {(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro- 2H-Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amide

Using Morpholine-4-Carboxyl Chloride [15159-40-7]

116 pentanoic acid {(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4- dihydro -2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amide

123 1-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-3-propylurea

Use Propylcarbamoyl Chloride [41891-16-1]

124 1-cyclopentyl-3-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}urea

Use cyclopentylcarbamoyl chloride [80413-7]

127 Cyclopentanecarboxylic acid {(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3- methoxypropyl )-3,4-dihydro-2H -Benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amide

Use cyclopentanecarbonyl chloride [4524-93-0]

128 N-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4- dihydro -2H- benzene And[1,4]oxazin-6-ylmethoxy]-piperidin-3-ylmethyl}-2,2-dimethyl-propionamide

Use pivaloyl chloride [3282-30-2]

129 {(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-methyl carbamate

Using methyl chloroformate [79-22-1]

133 1-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-3-methyl-urea

Use N-succinimidyl N-methylcarbamate [18342-66-0]

134 3-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-1,1-dimethyl-urea

Use N,N-dimethylcarbamoyl chloride [79-44-7]

130 N-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4- dihydro -2H- benzene And[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-butanamide

Using butyryl chloride [141-75-3]

131 N-((R)-2-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy- propyl )-3, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-methyl- ethyl )-isobutyramide

Using isobutyryl chloride [79-30-1], from (3S, 4R, 5R)-3-((S)-2-methanesulfonyloxy-propoxy)-4-(4-methoxy- Phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine- 1-Benzyl carboxylate to start.

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((S)-2-methanesulfonyloxy-propoxy)-4-(4- methoxyphenyl )-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From (3S, 4R, 5R)-3-((S)-2-hydroxy-propoxy)-4-(4-methoxy-phenyl)-5- in a manner similar to that used in Example 64b [4-(3-Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester The title compound was obtained as a brown oil. Rt = 5.24 (gradient I).

b) (3S, 4R, 5R)-3-((S)-2-hydroxy-propoxy)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

6.78 mmol of (3R,4R,5S)-4-(4-methoxy-phenyl)-3-[4-(3-methoxy-propyl) in 70 ml of ethanol was treated with 20.36 mmol of sodium borohydride -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((S)-1-oxiranylmethoxy)-piperidine-1 - Benzyl formate solution. The solution was stirred overnight at 45°C, cooled to room temperature, diluted with tert-butyl methyl ether and washed successively with saturated ammonium chloride solution, water and brine. The aqueous phase was extracted with dichloromethane (3x). The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.20 (EtOAc-heptane 2:1); Rt = 4.96 (gradient I).

c) (3R, 4R, 5S)-4-(4-methoxyphenyl))-3-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[ 1,4]oxazin-6-ylmethoxy]-5-((S)-1-oxiranylmethoxy)-piperidine-1-carboxylic acid benzyl ester

(3S, 4S, 5R)-3-hydroxy- 4-(4-methoxyphenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl Methoxy]-piperidine-1-carboxylic acid benzyl ester (Example 19c) afforded the title compound as a yellow oil. Rf = 0.18 (EtOAc-heptane 1:1); Rt = 5.12 (gradient 1).

132 N-((R)-2-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy- propyl )-3, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-methyl- ethyl )-propionamide

Using propionyl chloride [79-03-8], from (3S, 4R, 5R)-3-((S)-2-methanesulfonyloxy-propoxy)-4-(4-methoxy-benzene Base)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1 - Benzyl formate (example 131a) to start.

135 N-ethyl-N-((R)-2-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy- propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-methyl -ethyl)-ethyl Amide

From (3S, 4R, 5R)-3-((R)-2-ethylaminopropoxy)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

The starting materials were prepared as follows:

a) (3S, 4R, 5R)-3-((R)-2-ethylaminopropoxy)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester

1.82 mmol of (3S, 4R, 5R)-3-((S)-2-methanesulfonyloxy-propoxy)-4-(4-methoxybenzene) in 25 ml of ethanol was treated with 100.32 mmol of ethylamine Base)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1 - Benzyl formate (example 131a) solution. The solution was stirred at 50°C for 4 days, cooled to room temperature, evaporated and dissolved in tert-butyl methyl ether. The organic phase was washed successively with water and brine. The aqueous phase was extracted with tert-butyl methyl ether (3x). The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.16 (EtOAc-triethylamine 100:1); Rt = 4.61 (gradient I).

136 N-((R)-2-{(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy- propyl )-3, 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-1-methyl- ethyl )-N-propyl-ethyl Amide

By (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1, 4] Oxazin-6-ylmethoxy]-5-((R)-2-Propylamino-propoxy)-piperidine-1-carboxylic acid benzyl ester started.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1 ,4]oxazin-6-ylmethoxy]-5-((R)-2-propylamino-propoxy)-piperidine-1-carboxylic acid benzyl ester

(3S,4R,5R)-3-((S)-2-methanesulfonyloxypropoxy)-4-(4-methoxy- Phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine- Benzyl 1-carboxylate (Example 131a) afforded the title compound as a yellow oil. Rf = 0.19 (EtOAc-triethylamine 100:1); Rt = 4.75 (gradient I).

Example 93

(R)-1-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-3-methylbutylthio)-benzene Base]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-3- oxy)-propan-2-ol

Make 0.4mmol of (3R,4R,5S)-4-[4-((R)-4-methoxy-3-methylbutylsulfanyl)-phenyl]-3 in 4ml ethanol and 1ml tetrahydrofuran -[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1- Oxiranylmethoxy)piperidine-1-carboxylic acid methyl ester was mixed with 12 mmol of sodium borohydride. The reaction solution was stirred at 50° C. for 15 hours, and then mixed with 3 ml of dioxane, 3.6 ml of 40% aqueous potassium hydroxide solution and 1 ml of methanol. The reaction mixture was stirred at 90°C for 1 hour, then poured into water at room temperature and diluted with tert-butyl methyl ether. The aqueous phase was extracted with tert-butyl methyl ether (2x). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography ( _SiO2 60F).

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-((R)-4-methoxy-3-methylbutylthio)phenyl]-3-[4-(3- methoxy Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1-oxiranylmethoxy )piperidine -1-methyl carboxylate

0.5 mmol of (3S, 4S, 5R)-3-hydroxyl-4-[4-((R)-4-methoxy-3-methylbutylthio)-phenyl was prepared similarly to Example 36a ]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid The ester (Example 83a) was reacted with 1 mmol of (R)-1-oxiranylmethyltoluene-4-sulfonate [113826-06-5]. The title compound was identified by Rf.

The following compounds were prepared in a manner analogous to the method described in Example 93:

Example

94 (R)-1-{(3S,4R,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine- 6-ylmethoxy]-4-[4-(3-methoxypropylthio)phenyl]piperidin-3-yloxy}propan- 2-ol

95 (R)-1-{(3S, 4R, 5R)-4-[4-[4-methoxybutylthio)-phenyl]-5-[4-(3- methoxypropyl )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}propan-2-ol

102 (R)-1-{(3S,4R,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4]oxazine- 6-ylmethoxy]-4-[4-(3-methylthiopropoxy)phenyl]piperidin-3-yloxy}propan- 2-ol

From (3S, 4S, 5R)-3-hydroxy-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl Benzyl]-4-[4-(3-methylthiopropoxy)phenyl]piperidine-1-carboxylate (Example 80a) started.

Example 96

(S)-4-{(3S,4S,5R)-4-[4-(3-methoxypropoxy)phenyl]-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}butan-2-ol

From 0.63 g of (3S,4S,5R)-3-((S)-3-hydroxybutoxy)-4-[4-(3-methoxypropoxy)phenyl] analogously to method B -5-[4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl Esters to prepare the title compound.

The starting materials were prepared as follows:

a) (3S, 4S, 5R)-3-((S)-3-hydroxybutoxy)-4-[4-(3-methoxypropoxy) phenyl ]-5-[4-( 3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From 0.807 g of (3S, 4S, 5R)-3-[(S)-3-(tert-butyldimethylsilyloxy)butoxy]-4-[4-(3- Methoxypropoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy Benzyl]piperidine-1-carboxylate afforded the title compound as a yellow oil. Rf = 0.12 (EtOAc-heptane 2:1); Rt = 5.08 (gradient 1).

b) (3S, 4S, 5R)-3-[(S)-3-(tert-butyldimethylsilyloxy)butoxy]-4-[4-(3- methoxypropoxy) Phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethoxy]piperidine-1- Benzyl formate

0.15 g of sodium hydride (60% dispersion in oil) was added to 1.68 g of (3S,4S,5R)-3-hydroxy-4-[4-(3-methoxyl) in 10 ml of DMF at 0°C Propoxy)phenyl]-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piper Benzyl pyridine-1-carboxylate (Example 20b) was added to the solution, and the mixture was stirred for 1 hour. It was then cooled to -5°C, and 1.25 g of tert-butyl((S)-3-iodo-1-methylpropoxy)dimethylsilane [134510-70-6] was added dropwise over 1 hour. The reaction mixture was stirred at -5°C for 3 hours and then allowed to warm to room temperature. It was then diluted with tert-butyl methyl ether and poured into ice-water. The resulting mixture was extracted three times with tert-butyl methyl ether. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.45 (EtOAc-heptane 2:1).

The following compounds were prepared in a manner analogous to the method described in Example 96:

Example

97 (R)-4-{(3S, 4S, 5R)-4-[4-(3-methoxypropyl)phenyl]-5-[4-(3- methoxypropyl )-3 , 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}butan-2-ol

107 (S)-4-{(3S, 4S, 5R)-4-[4-(3-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}butan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

109 (R)-4-{(3S, 4S, 5R)-4-[4-(3-methoxybutoxy)phenyl]-5-[4-(3-methoxypropyl )- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yloxy}butan-2-ol

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylate (Example 78a) started.

Example 98

(R)-1-{(3S,4R,5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-2-ol

From 0.282 g of (3R,4R,5S)-4-[4-(4-methoxybutoxy)-phenyl]-3-[4-(3-methoxypropyl) in analogy to method B )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1-oxiranylmethoxy)piperidine- Benzyl 1-carboxylate to prepare the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5S)-4-[4-(4-methoxybutoxy)phenyl]-3-[4-(3- methoxypropyl )-3,4-dihydro -2H-Benzo[1,4]oxazin-6-ylmethoxy]-5-((R)-1-oxiranylmethoxy)piperidine -1-carboxylate

0.32 g of (3S, 4S, 5R)-3-hydroxyl-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 78a) and 0.227 (R)-1-oxiranylmethyltoluene-4-sulfonate [113826-06-5] reaction. The title compound was obtained as a pale yellow oil. Rf = 0.35 (EtOAc-heptane 2:1); Rt = 5.36 (gradient 1).

The following compounds were prepared in a manner analogous to the method described in Example 98:

Example 105

(S)-1-{(3S, 4R, 5R)-4-[4-(4-methoxybutoxy)phenyl]-5-[4-(3-methoxypropane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-2-ol

Using (S)-1-oxiranylmethyltoluene-4-sulfonate [70987-78-9]

Example 117

Tetrahydropyran-4-carboxylic acid {(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropane base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}amide

From (3R,4R,5R)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H- Benzo[1,4]oxazin-6-ylmethoxy]-5-{[(tetrahydropyran-4-carbonyl)amino]methyl}piperidine-1-carboxylic acid benzyl ester Preparation of the title compound.

The starting materials were prepared as follows:

a) (3R, 4R, 5R)-4-(4-methoxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro -2H-benzo[1 ,4]oxazin-6-ylmethoxy]-5-{[(tetrahydropyran-4-carbonyl)amino]-methyl}piperidine- 1-carboxylate benzyl ester

5 mmol of triethylamine and 1 mmol of propanephosphonic anhydride [68957-94-8, T3P] (50% in ethyl acetate) were continuously added to 1 mmol of (3R, 4R, 5R)-3 in 20 ml of dichloromethane at room temperature -Aminomethyl-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazine -6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 91b) and 1.1 mmol of tetrahydropyran-4-carboxylic acid [5337-03-1] solution. After 12 hours, the reaction mixture was diluted with dichloromethane and washed successively with 1N HCl and brine, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F). Rf = 0.13 (EtOAc); Rt = 4.63 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 117:

Example

118 2-cyclopentyl-N-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4-di Hydrogen-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}acetamide

Using Cyclopentylacetic Acid [1123-00-8]

119 (meso-1S, 5R, 6R)-3-oxabicyclo[3.1.0]hexa-6-carboxylic acid {(3S, 4R, 5R)-4-(4- methoxyphenyl)-5- [4-(3-Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy ]piperidin-3-ylmethyl}amide

(meso-1S,5R,6R)-3-oxabicyclo[3.1.0]hexa-6-carboxylic acid [55780-88-6] was used.

120 N-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-2-(meso-1R,5S,6S)-3-oxabicyclo [3.1.0]hexa- 6-ylacetamide

Using (meso-1R,5S,6S)-(3-oxabicyclo[3.1.0]hex-6-yl)acetic acid

The starting materials were prepared as follows:

a) (meso-1R, 5S, 6S)-(3-oxabicyclo[3.1.0]hex-6-yl)acetic acid

Add 3 mmol of triethylamine and 0.5 mmol of silver trifluoroacetate to 1 mmol of 1-diazo-3-(meso-1R,5S,6S)-3-oxo in 70 ml of 10:1 THF-water at -15 °C Heterobicyclo[3.1.0]hex-6-ylpropan-2-one solution. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. Diluted with tert-butyl methyl ether, washed with 1M HCl and brine, dried over sodium sulfate and evaporated. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

b) 1-diazo-3-(meso-1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylpropan-2-one

Add 1.2 mmol of triethylamine and 1 mmol of ethyl chloroformate to 1 mmol of (meso-1S, 5R, 6R)-3-oxabicyclo[3.1.0]hexa-6- Formic acid [55780-88-6] solution. The reaction mixture was warmed to -5°C and stirred at this temperature for 1 hour. Cool to -30°C, and add a 2.5 mmol solution of diazomethane in diethyl ether, and stir the mixture overnight. Diluted with tert-butyl methyl ether, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

121 4-Methoxycyclohexanecarboxylic acid {(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3- methoxypropyl )-3,4- Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-amide

Use 4-methoxycyclohexanecarboxylic acid [99183-14-9]

122 N-{(3S, 4R, 5R)-4-(4-methoxyphenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-ylmethyl}-2-(tetrahydropyran-4-yl)acetamide

Use (tetrahydropyran-4-yl)acetic acid [85064-61-5]

Example 138

N-{(3S, 4R, 5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy-propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-ylmethyl}-acetamide

From N-[(3R,4R,5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy- Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-ylmethyl ]-acetamide to give the title compound.

The starting materials were prepared as follows:

a) N-[(3R, 4R, 5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy- propyl)- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin- 3-ylmethyl]-acetamide

From toluene-4-sulfonic acid (3S, 4R, 5R)-4-[4-(4-methoxy-butoxy)-phenyl]- 5-[4-(3-Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4- Sulfonyl)-piperidin-3-ylmethyl ester afforded the title compound as a white foam. Rf=0.72 (dichloromethane-methanol-25% concentrated ammonia water=200:20:1); Rt=4.86 (gradient I).

b) Toluene-4-sulfonic acid (3S, 4R, 5R)-4-[4-(4-methoxybutoxy)-phenyl]-5-[4-(3- methoxypropyl) -3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin -3-ylmethyl ester

From [(3S,4R,5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy-propyl) analogously to method H )-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-yl]-methanol to obtain The title compound as a pale yellow oil. Rf = 0.46 (EtOAc-heptane = 2:1); Rt = 5.76 (gradient I).

c) [(3S, 4R, 5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy- propyl )-3, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)piperidin-3-yl] methanol

4-[(3S,4R,5R)-3-Hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-4-yl]-phenol and 1-bromo-3-methoxy-propane [4457 -67-4] The title compound was obtained in the form of a yellow oil. Rf = 0.28 (EtOAc-heptane = 2:1); Rt = 5.07 (gradient I).

d) 4-[(3S,4R,5R)-3-hydroxymethyl-5-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo [1,4] Oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-4-yl]-phenol

Make 1 mmol of [(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy- Propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-3-yl]- The methanolic solution was mixed with 5 mmol of sodium ethanethiolate, and the resulting suspension was heated at 130°C overnight. Diluted with 1N HCl and extracted with ethyl acetate (2x). The combined organic phases were dried over sodium sulfate and evaporated. The title compound is obtained as a yellow foam from the residue by flash chromatography ( _SiO2 60F). Rf = 0.13 (EtOAc-heptane = 2:1); Rt = 4.35 (gradient I).

e) [(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H- benzene And[1,4]oxazin-6-ylmethoxy-]-1-(toluene-4-sulfonyl)piperidin-3-yl]-methanol

From {(3S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3, 4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidin-3-yl}-methanol gave the title compound as a colorless oil. Rf = 0.25 (EtOAc-heptane = 2:1); Rt = 4.83 (gradient I).

f) {(3S, 4R, 5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo [1,4]oxazin-6-ylmethoxy]piperidin-3-yl}-methanol

From (3S,4R,5R)-3-hydroxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxypropyl)-3, Benzyl 4-dihydro-2b-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 87c) afforded the title compound as a yellow oil. Rt = 3.34 (gradient I).

The following compounds were prepared in a manner analogous to the method described in Example 138:

Example

144 N-{(3S, 4R, 5R)-4-[4-((S)-4-methoxy-3-methyl-butoxy) -phenyl ]-5-[4-(3- Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin- 3-ylmethyl}-acetamide

Use toluene-4-sulfonic acid (S)-4-methoxy-3-methyl-butyl ester

The starting materials were prepared as follows:

a) Toluene-4-sulfonic acid (S)-4-methoxy-3-methyl-butyl ester

The title compound was prepared analogously to method H from (S)-4-methoxy-3-methyl-butan-1-ol and determined from the residue by Rf by flash chromatography ( _SiO2 60F).

b) (S)-4-methoxy-3-methyl-butan-1-ol

A solution of 1 mmol of (S)-4-methoxy-3-methyl-butyronitrile in 10 ml of methanol and 10 ml of 2M aqueous sodium hydroxide solution was stirred at 80° C. for 16 hours. Most of the methanol was evaporated and the residual aqueous phase was acidified to pH 2 with 2M HCl solution and extracted with ethyl acetate (3 x 50ml). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

c) (S)-4-methoxy-3-methyl-butyronitrile

A mixture of 1 mmol of (R)-3-methoxy-2-methyl-propyl methanesulfonate and 5 mmol of sodium cyanide in 5 ml of dimethylsulfoxide was stirred at 60 °C for 16 h, then cooled to room temperature and added 10ml of water. The reaction mixture was extracted with tert-butyl methyl ether (3 x 50ml), dried over sodium sulfate and evaporated. The title compound was identified from the residue on the basis of Rf by flash chromatography ( _SiO2 60F).

d) Methanesulfonic acid (R)-3-methoxy-2-methyl-propyl ester

Add 2 mmol dropwise to a solution of 1 mmol (S)-3-methoxy-2-methyl-propan-1-ol [913969-31-0] and 5 mmol triethylamine in 10 ml dichloromethane at 0°C Methanesulfonyl chloride. The reaction mixture was stirred at 0°C for 3 hours, then the mixture was washed with water and 1M aqueous citric acid solution, dried over sodium sulfate and evaporated. The title compound is obtained as a colorless oil from the residue by flash chromatography ( _SiO2 60F) and is used unworked up in the next step. Rf = 0.57 (diethyl ether).

149 N-{(3S, 4R, 5R)-4-[4-((R)-4-methoxy-pentyloxy)-phenyl]-5-[4-(3-methoxy- propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-ylmethyl} -acetamide

Toluene-4-sulfonic acid (R)-4-methoxy-pentyl ester

The starting materials were prepared as follows:

a) Toluene-4-sulfonic acid (R)-4-methoxy-pentyl ester

The title compound was obtained from (R)-3-methoxy-butan-1-ol [119784-98-4] in a manner analogous to that described in Examples 144a, b, c and d and purified by flash chromatography. (SiO ₂ 60F) determined from the residue according to Rf.

Example 139

3-{(3S, 4S, 5R)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3-methoxy-propane Base)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-yloxy}-propan-1-ol

From (3S,4S,5R)-3-(3-hydroxy-propoxy)-4-[4-(4-methoxy-butoxy)-phenyl]-5-[ Preparation of the title compound from benzyl 4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate .

a) (3S, 4S, 5R)-3-(3-hydroxy-propoxy)-4-[4-(4-methoxy-butoxy) -phenyl ]-5-[4-(3 -Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1- carboxylic acid benzyl ester

From (3R,4S,5S)-4-[4-(4-methoxy-butoxy)-phenyl]-3-[4-(3-methoxypropyl)- 3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(3-triisopropylsilyloxy-propoxy)-piperidine-1- Benzyl formate afforded the title compound as a colorless oil. Rf = 0.06 (EtOAc-heptane 2:1); Rt = 5.01 (gradient 1).

b) (3R, 4S, 5S)-4-[4-(4-methoxy-butoxy)-phenyl]-3-[4-(3- methoxypropyl )-3,4- Benzyl dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(3-triisopropylsilyloxy-propoxy )-piperidine-1-carboxylate

From (3S, 4S, 5R)-3-hydroxy-4-[4-(4-methoxy-butoxy)-phenyl]-5-[4-(3- Methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylic acid benzyl ester (Example 78a) gave colorless The title compound as an oil. Rf = 0.25 (EtOAc-heptane 1:1); Rt = 8.04 (gradient III).

Claims (11)

1. the compound of following general formula, and salt, preferred its pharmacologically acceptable salt,

Wherein

(A) R ¹Be the heterocyclic radical that replaces by oxo or oxide compound, perhaps be following (B) or (C) expression heterocyclic radical, azepan base particularly, benzo [1,3] dioxolyl, benzofuryl, benzimidazolyl-, 4H-benzo [1,4] oxazinyl benzoxazolyls, 4H-benzo [1,4] thiazinyl, quinolyl, benzopyranyl, dihydro-benzo [e] [1,4] diazacyclo heptenyl, dihydro benzo furyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydrobenzo [d] [1,3] oxazinyl, 3,4-dihydro-2H-benzo [1,4] thiazinyl, dihydro-2H-1 λ 6-benzo [1,4] thiazinyl, dihydro-1H-quinazolyl, 1a, 7b-dihydro-1H-encircles third [c] benzopyranyl, the glyoxalidine base, 1, the 3-indolinyl, 2, the 3-indolinyl, dihydro-1H-pyrido [2,3-b] [1,4] oxazinyl, indazolyl, indyl, the 3H-isobenzofuran-base, [1,5] phthalazinyl oxazolyl, 2, the 3-phthalazinyl, piperidyl, pyrazolyl, 1H-pyrido [2,3-b] [1,4] oxazinyl, pyridyl, the 1H-pyrrolidyl, 1H-pyrrolo-[2,3-b] pyridyl, pyrryl, tetrahydro benzo [e] [1,4] diazacyclo heptenyl, 3H-thieno-[2,3-d] pyrimidyl, tetrahydrochysene-quinoxalinyl, 1,1a, 2,7b-tetrahydrochysene ring third [c] benzopyranyl, THP trtrahydropyranyl or triazinyl; Or

(B) R ¹The aryl that the following group of serving as reasons replaces: 1-4-ethanamidine base-C _1-8Alkyl, acyl group-C _1-8Alkoxy-C _1-8Alkyl, (N-acyl group)-C _1-8Alkoxy-C _1-8Alkylamino, C _1-8Alkoxyl group, C _1-8Alkoxy-C _1-8Alkoxyl group, C _1-8Alkoxy-C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkoxy-C _1-8Alkyl, (N-C _1-8Alkoxyl group)-C _1-8Alkyl amino-carbonyl-C _1-8Alkoxyl group, (N-C _1-8Alkoxyl group)-C _1-8Alkyl amino-carbonyl-C _1-8Alkyl, C _1-8Alkoxy-C _1-8Alkyl-formamyl, C _1-8Alkoxy-C _1-8Alkyl-carbonyl, C _1-8Alkoxy-C _1-8Alkyl-carbonyl-amino, 1-C _1-8Alkoxy-C _1-8Alkyl imidazole-2-base, 2-C _1-8Alkoxy-C _1-8Alkyl-4-oxo-imidazole-1-base, 1-C _1-8Alkoxy-C _1-8-alkyl tetrazolium-5-base, 5-C _1-8Alkoxy-C _1-8-alkyl tetrazolium-1-base, 6-alkoxyl group-aminocarboxyl-C _1-8Alkoxyl group, C _1-8Alkoxy amino carbonyl-C _1-8Alkyl, C _1-8Alkoxy carbonyl, C _1-8Alkoxy carbonyl-C _1-8Alkoxyl group, C _1-8Alkoxy carbonyl-C _1-8Alkyl, C ₁- ₈Alkoxycarbonyl amino-C _1-8Alkoxyl group, C _1-8Alkoxycarbonyl amino-C _1-8Alkyl, C _1-8Alkyl, (N-C _1-8Alkyl)-C _1-8Alkoxy-C _1-8Alkyl-carbamoyl, (N-C _1-8Alkyl)-C _1-8Alkoxy-C _1-8Alkyl-carbonyl-amino, (N-C _1-8Alkyl)-C _1-8Alkoxycarbonyl amino, (N-C _1-8Alkyl)-C _0-8Alkyl-carbonyl-amino-C _1-8Alkoxyl group, (N-C _1-8Alkyl)-C _0-8Alkyl-carbonyl-amino-C _1-8Alkyl, (N-C _1-8Alkyl)-C _1-8Alkyl sulfonyl-amino-C _1-8Alkoxyl group, (N-C _1-8Alkyl)-C _1-8Alkyl sulfonyl-amino-C _1-8Alkyl, C _1-8Alkyl amidine, C _1-8Alkyl amino-carbonyl-C _1-8Alkoxyl group, two-C _1-8Alkyl amino-carbonyl-C _1-8Alkoxyl group, C _1-8Alkyl amino-carbonyl-C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkyl amino-carbonyl-C _1-8Alkyl, C _1-8Alkyl amino-carbonyl amino-C _1-8Alkoxyl group, C _1-8Alkyl amino-carbonyl amino-C _1-8Alkyl, two-C _1-8Alkyl amino-carbonyl-C _1-8Alkyl, C _1-8Alkylamino-C _2-8Alkoxyl group, two-C _1-8Alkylamino-C _2-8Alkoxyl group, C _1-8Alkylamino-C _1-8Alkyl, two-C _1-8Alkylamino-C _1-8Alkyl, C _1-8Alkyl-carbamoyl, two-C _1-8Alkyl-carbamoyl, C _0-8Alkyl-carbonyl-amino-C _1-8Alkoxyl group, C _0-8Alkyl-carbonyl-amino, C _0-8Alkyl-carbonyl-amino-C _1-8Alkyl, C _1-8Alkyl carbonyl oxy-C _1-8Alkoxyl group, C _1-8Alkyl carbonyl oxy-C _1-8Alkyl, C _1-8Alkyl sulphonyl, C _1-8Alkyl sulphonyl-C _1-8Alkoxyl group, C _1-8Alkyl sulphonyl-C _1-8Alkyl, C _1-8Alkyl sulfonyl-amino-C _1-8Alkoxyl group, C _1-8Alkyl sulfonyl-amino-C _1-8Alkyl, formamyl, formamyl-C _1-8Alkoxyl group, formamyl-C _1-8Alkyl, carboxyl-C _1-8Alkoxyl group, carboxyl-C _1-8Alkoxy-C _1-8Alkyl, carboxyl-C _1-8Alkyl, cyano group, cyano group-C _1-8Alkoxyl group, cyano group-C _1-8Alkyl, C _3-8Cycloalkyl-C _1-8Alkoxyl group, C _3-8Cycloalkyl-C _1-8Alkyl, C _3-8Cycloalkyl amino carbonyl-C _1-8Alkoxyl group, C _3-8Cycloalkyl amino carbonyl-C _1-8Alkyl, O, N-dimethyl hydroxyl amino-C _1-8Alkyl, halogen, hydroxyl-C _1-8Alkoxy-C _1-8Alkoxyl group, hydroxyl-C _1-8Alkoxy-C _1-8Alkyl, hydroxyl-C _1-8Alkyl, (N-hydroxyl)-C _1-8Alkyl amino-carbonyl-C _1-8Alkoxyl group, (N-hydroxyl)-C _1-8Alkyl amino-carbonyl-C _1-8Alkyl, (N-hydroxyl) aminocarboxyl-C _1-8Alkoxyl group, (N-hydroxyl) aminocarboxyl-C _1-8Alkyl, 2-Yang Dai oxazolidinyl-C _1-8Alkoxyl group, 2-Yang Dai oxazolidinyl-C _1-8Alkyl, O-methyl oximido-C _1-8Alkyl, many halo-C _1-8Alkoxyl group or many halo-C _1-8Alkyl; Or

(C) R ¹The aryl that the following group of serving as reasons replaces: 3-acetamidomethyl pyrrolidyl, 3-C _1-8Alkoxy-C _1-8Alkyl-pyrrolidyl, 3,4-dihydroxy-pyrrolidine alkyl, 2, the 6-dimethylated morpholinyl, 3, the 5-dimethylated morpholinyl, the dioxane base, dioxolanyl, 4,4-dioxo thio-morpholinyl, the dithiane base, the dithiolane base, 2-hydroxymethyl pyrrolidine base, 4-hydroxy piperidine base, 3-hydroxyl pyrrolidine base, imidazolyl-alkoxyl group, the imidazolyl alkyl, glyoxal ethyline base alkoxyl group, glyoxal ethyline base alkyl, 3-methyl-[1,2,4]-oxadiazoles-5-base alkoxyl group, 5-methyl-[1,2,4]-oxadiazoles-3-base alkoxyl group, 3-methyl-[1,2,4]-oxadiazoles-5-base alkyl, 5-methyl-[1,2,4]-oxadiazoles-3-base alkyl, 4-methylpiperazine base, 5-methyl tetrazolium-1-base alkoxyl group, 5-methyl tetrazolium-1-base alkyl, morpholinyl, [1,2,4]-oxadiazoles-5-base alkoxyl group, [1,2,4]-oxadiazoles-5-base alkyl oxazole-4-base alkoxyl group oxazole-4-base alkyl, 2-oxo-[1,3]-oxazinyl, 2-Yang Dai oxazolidinyl, 2-oxo-imidazole alkyl, 2-oxo-pyrrolidine base, 4-oxo-piperidyl, 2-oxo-pyrrolidine base alkoxyl group, 2-oxo-pyrrolidine base alkyl, 2-oxo tetrahydro-pyrimidine base, 4-oxo thio-morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrryl, [1,2,4]-triazol-1-yl-alkoxyl group, [1,2,4]-triazole-4-base alkoxyl group, [1,2,4]-the triazol-1-yl alkyl, [1,2,4]-triazole-4-base alkyl, tetrazolium-1-base alkoxyl group, tetrazolium-2-base alkoxyl group, tetrazolium-5-base alkoxyl group, tetrazolium-1-base alkyl, tetrazolium-2-base alkyl, tetrazolium-5-base alkyl, thiazole-4-base alkoxyl group, thiazole-4-base alkyl or thio-morpholinyl; Or

(D) as X be-O-CHR ⁶-CO-NR ⁴-R ¹Or-O-CHR ⁶-CO-NR ⁴-Z, wherein Z is Alk-R ¹, wherein Alk is C _1-8During alkylidene group, R ¹Be aryl; Or

(E) when X be-O-Z that wherein Z is Alk-NR ⁴-R ¹, or X is-Z that wherein Z is-Alk-NR ⁴-R ¹, wherein Alk is C _1-8During alkylidene group, R ¹Be aryl;

R ²A) when W is cyano group, there is not R ²Or

B) when W be-O-or-during S-, R ²Be C ^1-8Alkyl, C _2-8Thiazolinyl, C _2-8Alkynyl, C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkoxy-C _3-8Cycloalkyl-C _1-8-alkyl, C _1-8Alkylthio-C _1-8Alkyl, C _1-8Alkyl sulphonyl-C _1-8Alkyl;

R ³A) be halogen-and/or the C of hydroxyl-replacement _1-8Alkoxyl group, halogen-and/or the C of hydroxyl-replacement _1-8Alkoxy-C _1-8Alkoxyl group, branching C _1-8Alkoxy-C _1-8Alkoxyl group, optional N-list or N, N-two-C _1-8-alkylation amino-C _1-8Alkoxyl group, optional N-C _1-8Alkylation C _1-8Alkoxy-C _1-8Alkylamino-C _1-8Alkoxyl group, optional N-list or N, N-two-C _1-8Alkylation amino-C _0-8-alkyl-carbonyl-C _1-8Alkoxyl group, hydroxyl-C _0-8-alkyl-carbonyl-C _0-8Alkoxyl group, C _1-8Alkoxy-C _0-8Alkyl-carbonyl-C _0-8Alkoxyl group, C _1-8-alkyl-carbonyl-amino-C _1-8Alkoxyl group, cyano group-C _1-8The C of alkoxyl group, replacement _3-8Cycloalkyl-C _0-8Alkoxyl group, heterocyclic radical-C _0-8Alkoxyl group, optional N-C _1-8Alkylated heterocyclic base-C _0-8Alkylamino-C _0-8Alkyl-carbonyl-C _0-8Alkoxyl group, C _1-8Alkyl-alkylsulfonyl-C _1-8Alkoxyl group, C _2-8Alkynyloxy group, heterocyclic radical-C _2-8Alkynyloxy group, optional N-list or N, N-two-C _1-8Alkylation amino-C _2-8Alkynyloxy group, N-list or N, N-two-C _1-8Alkylation aminocarboxyl-C _2-8Alkynyloxy group, heterocyclic radical carbonyl-C _0-8Alkoxyl group, optional N-list or N, N-two-C _1-8Alkylation amino-C _1-8Alkyl, optional N-C _1-8Alkylation C _1-8Alkoxy-C _1-8Alkylamino-C _1-8Alkyl, optional N-list or N, N-two-C _1-8Amino-C that alkylation and optional hydroxyl replace _0-8Alkyl-carbonyl-C _0-8Alkyl, optional N-C _1-8Alkylated heterocyclic base-C _0-8Alkylamino-C _0-8Alkyl-carbonyl-C _0-8The C that alkyl, optional halogen or hydroxyl replace _1-8Alkoxy-C _1-8Hydroxyl-C that alkyl, optional halogen or hydroxyl replace _1-8Alkyl, optional N-C _1-8Alkylate hydroxyl-C _1-8Alkylamino-C _1-8Alkyl, heterocyclic radical carbonyl-C _0-8Alkyl, heterocyclic radical carbonyl-C _0-8Alkylamino-C _1-8Alkyl, heterocyclic radical-C _1-8Alkyl, C _1-8Alkoxycarbonyl amino-C _1-8Heterocyclic radical-C that alkyl, optional halogen replace _0-8Alkyl-carbonyl-amino-C _1-8The C that alkyl, optional halogen replace _3-8Cycloalkyl-C _0-8Alkyl-carbonyl-amino-C _1-8The C that alkyl or optional halogen replace _1-8Alkyl-carbonyl-amino-C _1-8Alkyl; Or in addition

B) if-W-R ²Not C _1-8Alkoxyl group, then R ³Be hydroxyl, unsubstituted C _1-8Alkoxyl group, unsubstituted nonbranched C _1-8Alkoxy-C _1-8-alkoxyl group or unsubstituted C _3-8Cycloalkyl-C _0-8Alkoxyl group;

R ⁴Be acyl group, C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkyl, aryl-C _1-8Alkyl, C _3-8Cycloalkyl-C _0-8Alkyl or hydrogen;

R ⁵Be C _1-8Alkoxy carbonyl-C _1-8Alkyl, C _1-8Alkyl, carboxyl-C _1-8Alkyl or hydrogen;

R ⁶Be acyl group, C _2-8Thiazolinyl, C _1-8Alkyl, aryl-C _1-8Alkyl or hydrogen;

X be Z ,-O-Z or-S-Z, the key that wherein derives from oxygen or sulphur atom produces the saturated C atom of group Z, or is group-CHR ⁶-Z ,-CHOR ⁴-Z ,-O-CO-Z ,-O-CO-R ¹,-CO-Z ,-C=NOR ⁵-Z ,-O-CHR ⁶-Z ,-O-CHR ⁶-CO-NR ⁴-Z ,-O-CHR ⁶-CO-NR ⁴-R ¹, or-O-CHR ⁶-R ¹

W is-O-,-S-or cyano group;

Z is C _1-8-Alk-R ¹, C _2-8Alkenylene-R ¹, hydroxyl-replacement-Alk-R ¹,-O-R ¹,-S-R ¹,-O-Alk-R ¹,-S-Alk-R ¹,-Alk-O-R ¹,-Alk-S-R ¹Or-Alk-NR ⁴-R ¹, wherein Alk is C _1-8Alkylidene group; Wherein

(a) if Z be-O-R ¹Or-S-R ¹, then X is-CH-R ⁶-Z;

(b) if Z be-O-Alk-R ¹Or-S-Alk-R ¹, then X is-CH-R ⁶-Z; With

(c) if X is Z, then Z is C _2-8Alkenylene-R ¹,-Alk-O-R ¹,-Alk-S-R ¹Or-Alk-NR ⁴-R ¹

2. according to the compound of claim 1, it is corresponding to general formula (IA)

And salt, preferably its pharmacologically acceptable salt, wherein substituent R ², R ³, W and X implication identical with implication according to the compound of the formula (I) of claim 1.

3. according to the compound of claim 1 or 2, wherein

X is-CHR ⁶-Alk-R ¹,-Alk-NR ⁴-R ¹,-Alk-O-R ¹,-Alk-S-R ¹, C _2-8-alkenylene-R ¹,-CH (OR ⁴)-Alk-R ¹,-CHR ⁶-Alk-R ¹,-CHR ⁶-O-R ¹,-CHR ⁶-O-Alk-R ¹,-CHR ⁶-S-R ¹,-CHR ⁶-S-Alk-R ¹,-CO-Alk-R ¹,-C (=NOR ⁵)-Alk-R ¹,-O-Alk-NR ⁴-R ¹,-O-Alk-R ¹,-O-Alk-O-R ¹,-O-CO-R ¹,-O-CO-Alk-R ¹,-O-CHR ⁶-R ¹,-O-CHR ⁶-Alk-R ¹,-O-CHR ⁶-CO-NR ⁴-R ¹Or-O-CHR ⁶-CO-NR ⁴-Alk-R ¹, wherein Alk is C _1-8Alkylidene group.

4. according to each compound of claim 1 to 3, wherein

R ³A) be halogen-and/or the C of hydroxyl-replacement _1-8Alkoxyl group, halogen-and/or the C of hydroxyl-replacement _1-8Alkoxy-C _1-8Alkoxyl group, branching C _1-8Alkoxy-C _1-8Alkoxyl group, optional N-list or N, N-two-C _1-8Alkylation amino-C _1-8Alkoxyl group, optional N-list or N, N-two-C _1-8Alkylation amino-C _0-8Alkyl-carbonyl-C _1-8The C of alkoxyl group, replacement _3-8Cycloalkyl-C _0-8Alkoxyl group, optional C _1-8Heterocyclic radical-the C of alkoxyl group or hydroxyl-replacement _0-8Alkoxyl group, heterocyclic radical carbonyl-C _0-8Alkoxyl group, heterocyclic radical carbonyl-C _0-8Heterocyclic radical-C that alkyl, optional halogen replace _0-8Alkyl-carbonylamino-C _1-8The C that alkyl, optional halogen replace _3-8Cycloalkyl-C _0-8Alkyl-carbonyl-amino-C _1-8The C that alkyl or optional halogen replace _1-8Alkyl-carbonyl-amino-C _1-8Alkyl; Or in addition

B) if-W-R ²Not C _1-8Alkoxyl group, then R ³Be hydroxyl, unsubstituted C _1-8Alkoxyl group, do not replace nonbranched C _1-8Alkoxy-C _1-8-alkoxyl group or unsubstituted C _3-8Cycloalkyl-C _0-8Alkoxyl group.

5. according to each compound of claim 1 to 4, wherein

R ²Be C _1-8Alkyl, C _2-8Thiazolinyl, C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkoxy-C _3-8Cycloalkyl-C _1-8Alkyl, C _3-8Cycloalkyl-C _0-8Alkoxy-C _1-8Alkyl, C _1-8Alkylthio-C _1-8Alkyl, C _1-8Alkyl sulphonyl-C _1-8Alkyl;

R ³A) be the C of hydroxyl-replacement _1-8The C of alkoxyl group, hydroxyl-replacement _1-8Alkoxy-C _1-8Alkoxyl group, branching C _1-8Alkoxy-C _1-8Alkoxyl group or C _1-8Alkyl-carbonyl-amino-C _1-8Alkyl; Or in addition

B) if R ²Not C _1-8Alkyl, then R ³Be hydroxyl, unsubstituted C _1-8Alkoxyl group or do not replace nonbranched C _1-8Alkoxy-C _1-8Alkoxyl group;

With

W is-O-.

6. according to each compound of claim 1 to 5, wherein

R ¹Be the benzopyranyl or 3 that replaces, 4-dihydro-2H-benzo [1,4] oxazinyl;

R ²Be C _1-8Alkyl, C _2-8Thiazolinyl, C _1-8Alkoxy-C _1-8Alkyl, C _1-8Alkoxy-C _3-8Cycloalkyl-C _1-8Alkyl, C _3-8Cycloalkyl-C _0-8Alkoxy-C _1-8Alkyl, C _1-8Alkylthio-C _1-8Alkyl;

R ³A) be the C of hydroxyl-replacement _1-8The C of alkoxyl group, hydroxyl-replacement _1-8Alkoxy-C _1-8Alkoxyl group, branching C _1-8Alkoxy-C _1-8Alkoxyl group or C _1-8Alkyl-carbonyl-amino-C _1-8Alkyl; Or in addition

B) if R ²Not C _1-8Alkyl, then R ³Be hydroxyl, unsubstituted C _1-8Alkoxyl group or do not replace nonbranched C _1-8Alkoxy-C _1-8Alkoxyl group;

R ⁶Be C _1-8Alkyl or hydrogen;

X is-CHR ⁶-Alk-R ¹Or-O-Alk-R ¹, wherein Alk is C _1-8Alkylidene group; With

W is-O-.

7. the purposes that is used to produce medicine according to each the compound or pharmaceutically acceptable salt thereof of general formula (I) of claim 1 to 6.

According to each the compound or pharmaceutically acceptable salt thereof of general formula (I) of claim 1 to 6 be used to produce prevention, delay hypertension, the development of heart failure, glaucoma, myocardial infarction, renal failure, restenosis or apoplexy or be used for the treatment of the purposes of the human medicine of hypertension, heart failure, glaucoma, myocardial infarction, renal failure, restenosis or apoplexy.

9. method that is used to prevent, delay the development of hypertension, heart failure, glaucoma, myocardial infarction, renal failure, restenosis or apoplexy or is used for the treatment of hypertension, heart failure, glaucoma, myocardial infarction, renal failure, restenosis or apoplexy, wherein use the treatment significant quantity according to each the compound or pharmaceutically acceptable salt thereof of general formula (I) of claim 1 to 6.

10. medicament comprises according to each the compound or pharmaceutically acceptable salt thereof of general formula (I) of claim 1 to 6, and conventional excipients.

11. the product of forming by independent component or the drug regimen of kit form, described independent component by a) according to each the compound or pharmaceutically acceptable salt thereof of general formula (I) of claim 1 to 6, and b) at least a medicament forms as activeconstituents with cardiovascular effect forms.